Stem Cell Research,
Tracked in Real Time.

Guangzhou FineImmune Biotechnology Co., LTD.

This study was a phase I safety and tolerability clinical trial conducted in a single-center, open-label, 3+3 design with dose escalation. Phase: PHASE1 Status: RECRUITING Conditions: Advanced Hepatocellular Carcinoma (HCC); GPC3 Positive Hepatocellular Carcinoma Interventions: Super CAR-T

Multiple Myeloma Research Consortium

The Multiple Myeloma Research Consortium (MMRC) Horizon Two trial is a master protocol, multi-center, phase II randomized adaptive platform trial designed to efficiently evaluate multiple investigational therapies in high-risk newly diagnosed multiple myeloma patients using an integrated and patient-centric clinical research platform that enables longitudinal learning and sharing of knowledge and investigates multiple novel therapeutic strategies within one trial platform. Phase: PHASE2 Status: RECRUITING Conditions: High Risk Newly Diagnosed Multiple Myeloma Interventions: Bispecific Monoclonal Antibody and Triplet Therapy; Monoclonal Antibody with Stem Cell Transplant

Xiaoping Liu, Dandan Wang, Lei Jia et al.

Mitochondrial dysfunction contributes to poor embryo quality and recurrent assisted reproductive technology (ART) failure. Mitochondrial transplantation (MIT), which involves supplementing oocytes with exogenous mitochondria, has been proposed as a novel strategy to improve ART outcomes. However, both its clinical efficacy and safety remain unclear.

Lei Lei, Masako M Kaufmann, Jessica Lao et al.

Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.

Junye Chen, Kang Li, Jiang Shao et al.

Atherosclerotic carotid stenosis is a major cause of stroke, yet the mechanisms driving plaque instability remain incompletely understood. Perivascular adipose tissue (PVAT), the fat surrounding blood vessels, has been implicated in advanced atherosclerosis progression, but its cellular contributions are largely unknown. Here we show that PVAT contains two distinct adipose-derived stem cell (ADSC, multipotent progenitor cells within fat tissue) subsets. By analyzing 169 clinical samples using single-cell RNA sequencing and flow cytometry and pathological staining, we identify CD55⁺ADSCs as elevated in patients with symptomatic carotid stenosis or prior stroke. These cells migrate into plaques, differentiate into endothelial cells and promote pathological angiogenesis and vascular remodeling through FGF2 secretion thereby destabilising plaques. A second population, CXCL14+ADSCs exacerbate inflammation by recruiting immune cells via the CXCL12-CXCR4 axis. Our findings identify perivascular CD55+ADSCs as a therapeutic target for atherosclerosis management.

Kristina Roth, Dennis Loeffler, Conny Blumert et al.

Abstract Graft-versus-host disease (GVHD) remains one of the major complications following allogeneic hematopoietic cell transplantation. Currently, immunosuppressants are used for GVHD prophylaxis and treatment in most transplantation recipients. Due to their systemic, nonspecific mode of action, this treatment regimen is frequently associated with severe toxic side effects, opportunistic infections, as well as cancer relapse when treating hematologic malignancies. By using short-term ex vivo modulation of hematopoietic cell transplants with the anti-human CD4 antibody MAX.16H5, we have developed a novel immune tolerance–inducing strategy enabling potent GVHD prevention. Functional in vitro assays and transcriptome profiling data suggest impaired T-cell receptor signaling and a shift toward an interleukin-10–dependent regulatory phenotype as the primary mechanism of action of anti-human CD4 antibody treatment, leading to significantly reduced activation and proliferation of CD4+ and CD8+ T cells. A one-time incubation of hematopoietic transplants with MAX.16H5 prolongs survival of NSG (NOD.Cg-PrkdcSCID Il2rgtm1Wjl/SzJ) mice and reduces signs of GVHD manifestation as effectively as repeated application with clinically applied immunosuppressants, making it a safe and effective immunotherapy for GVHD prevention.

Grayson E. Rodriguez, Yang Zhao, Yoko Nishiga et al.

Cytokines dimerize two receptor chains to activate Janus kinases and signal transducer and activator of transcription (STAT) transcription factors that regulate immune cells, but they have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs. Trikines coactivated phosphorylation of STAT5 (pSTAT5) and pSTAT3 signatures distinct from natural cytokines by assembling trimeric combinations of interleukin-2 (IL-2), IL-10, and IL-21 receptors. In preclinical models, an IL-2–based Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without observable toxicity. An IL-10–based Trikine induced immune infiltration into poorly immunogenic tumors, showing efficacy in preclinical models of small cell lung cancer and pancreatic cancer. Trikines obviate the need for cell engineering to customize STAT signatures and may hold potential for immunotherapy.

National Cancer Institute (NCI)

Background: Small cell lung cancer (SCLC) is the deadliest form of lung cancer. Extrapulmonary neuroendocrine cancer (EPNEC) is a similar type of cancer that develops anywhere other than the lungs. EPNEC is also deadly. B7-H3 is a protein often found in SCLC and EPNEC tumor cells. Researchers can modify a person s own T cells, or immune cells, to target B7-H3. When these modified T cells are returned to the body-a treatment called B7-H3 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells. Objective: To test B7-H3 CAR T cell therapy in people with SCLC or EPNEC. Eligibility: People aged 18 years and older with SCLC or EPNEC that either did not respond or returned after treatment. Design: Participants will be screened. They will have blood tests and tests of their heart function. They will have imaging scans. Participants will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be altered to make them attack cells with B7-H3. Participants will be in the hospital for at least 15 days. They will receive chemotherapy drugs to prepare their body for the treatment. These drugs will be given through a tube attached to a needle inserted into a vein. The modified T cells will be infused through a vein. Participants will remain in the hospital until they are well enough to go home. Follow-up visits will continue for 15 years.... Phase: PHASE1 Status: NOT_YET_RECRUITING Conditions: Extensive-Stage Small Cell Lung Cancer; Extrapulmonary Neuroendocrine Carcinoma; Recurrent or Refractory; Solid Tumors Interventions: Autologous B7-H3 CAR T; Cyclophosphamide; Fludarabine

Aspen Neuroscience

This clinical trial is designed to test the safety and tolerability of injecting ANPD001 cells that will mature into dopamine-producing cells into the brain of participants with Parkinson Disease. All participants will have ANPD001 cells manufactured from their own previously collected cells. Phase: PHASE1 Status: ENROLLING_BY_INVITATION Conditions: Parkinson Disease Interventions: ANPD001; Custom Device

Liping Dou

The purpose of this study is to determine the efficacy and safety of CD19/CD22 Chimeric Antigen Receptor (CAR) T-Cell immunotherapy as first-line consolidation therapy in patients with follicular lymphoma. Phase: PHASE2 Status: RECRUITING Conditions: Lymphoma Interventions: CD22/CD19 CAR-T cell immunotherapy

National Cancer Institute (NCI)

This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma. Phase: PHASE3 Status: RECRUITING Conditions: Ganglioneuroblastoma, Nodular; Neuroblastoma Interventions: Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Carboplatin; Cisplatin; Computed Tomography; Cyclophosphamide; Dinutuximab; Doxorubicin; Echocardiography Test; Etoposide; FDG-Positron Emission Tomography and Computed Tomography Scan; Hematopoietic Cell Transplantation; Irinotecan; Isotretinoin; Leukapheresis; Magnetic Resonance Imaging; Melphalan; Multigated Acquisition Scan; Radiation Therapy; Radionuclide Imaging; Survey Administration; Temozolomide; Thiotepa; Topotecan; Tumor Resection; Vincristine

Kyverna Therapeutics

A Study of the Anti-CD 19 Chimeric Antigen Receptor T Cell Therapy for Patients with Myasthenia Gravis Phase: PHASE2, PHASE3 Status: RECRUITING Conditions: Myasthenia Gravis; Generalized Myasthenia Gravis Interventions: Standard of Care Treatment; Standard lymphodepletion regimen; KYV-101

National Cancer Institute (NCI)

This phase II trial compares iberdomide maintenance therapy to disease monitoring for improving survival in patients who have received idecabtagene vicleucel (a type of chimeric antigen receptor T-cell \[CAR-T\] therapy) for multiple myeloma. The usual approach after treatment with idecabtagene vicleucel is to monitor the multiple myeloma without giving myeloma medications. There is currently no medication approved specifically for use after idecabtagene vicleucel treatment. Upon administration, iberdomide modifies the immune system and activates immune cells called T-cells, which could enhance the effectiveness of idecabtagene vicleucel. Iberdomide may keep multiple myeloma under control for longer than the usual approach (disease monitoring) after idecabtagene vicleucel, and may help multiple myeloma patients live longer. Phase: PHASE2 Status: RECRUITING Conditions: Multiple Myeloma Interventions: Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Computed Tomography; Iberdomide; Magnetic Resonance Imaging; Patient Monitoring; Positron Emission Tomography; Skeletal Survey X-Ray

Zhejiang Cancer Hospital

This is a prospective, single-arm, single-center, open-label clinical study, aiming to evaluate the efficacy and safety of CAR-T combined with ASCT in the treatment of relapsed/refractory large B-cell lymphoma with high-risk factors. Phase: PHASE2 Status: RECRUITING Conditions: High-risk R/R LBCL Interventions: Axicabtagene Ciloleucel

Masahito Kawabori, Kenji Hirata, Hideo Shichinohe et al.

Ischemic stroke is a leading cause of mortality and long-term neurological disability worldwide, and cell-based therapies represent a promising approach. Although clinical studies have reported favorable outcomes following cell transplantation, the effects on host neuronal integrity remain incompletely understood. This study investigated temporal and spatial changes in fluorodeoxyglucose positron emission tomography (FDG-PET) and 123I-iomazenil single-photon emission computed tomography (IMZ-SPECT) after intracerebral cell transplantation in patients with subacute ischemic stroke and examined their relationship with functional recovery. Seven adults with severe post-stroke disability underwent autologous mesenchymal stromal cell (HUNS001-01) transplantation 47-64 days after stroke onset. Brain FDG-PET and IMZ-SPECT were performed preoperatively and at 1, 3, and 12 months post-transplantation. Regions of interest were first manually set in the ipsilateral cortex where the 12-month postoperative-to-preoperative standard uptake value ratio seems increased, and followed by quantitative measurement. Five of seven patients demonstrated 5% or more increase of FDG-PET and/or IMZ-SPECT uptake in peri-infarct cortical regions, predominantly within the frontal or temporal cortex. Transplanted cells localized either within metabolically enhanced regions or in anatomically remote areas. FDG-PET and IMZ-SPECT changes were strongly interacted in each other and were associated with functional improvement. Overall, improvement of glucose metabolism and synaptic density/viability were observed in patient with subacute ischemic stroke, which may have been attributable to cell transplantation.Trial registration: UMIN000026130.

Yajie Zhu, Konstantinos Sofiadis, Athanasia Mizi et al.

The maintenance of stem cell identity, as well as the differentiation of stem cells into any lineage, requires precise regulation of gene expression. Despite intensive research, our understanding of these regulatory processes remains incomplete. Here, we focus on the understudied paralogs of the U1 small nuclear RNA gene known as variant U1 snRNAs. By generating isogenic knockout lines of human induced pluripotent stem cells for different variant U1s, we show that their loss profoundly changes both gene expression and cell cycle profiles. These effects manifest alongside alternative splicing patterns, including those involving recursive splicing sites, and lead to differential availability of stem cell regulators. Together, our results shed new light on the functional roles of variant U1 snRNAs and further our understanding of the programs controlling human pluripotency.

Wentao Xu, Huina Li, Wei Zhang et al.

TDP43 inclusion bodies are widely present in the majority of patients with familial and sporadic amyotrophic lateral sclerosis (ALS). The mechanisms regulating TDP43 solubility remain incompletely understood. Here, we report that TDP43 undergoes S-acylation primarily at the Cys244 residue by the S-acyltransferase zDHHC23. This S-acylation maintains the liquid-like properties of TDP43 by reducing the aberrant interaction with poly(ADP-ribose) polymerase 1 (PARP1) and PARylated proteins, thereby countering the pathological condensation of TDP43. S-acylation-deficient TDP43 inclusions sequester the translational machinery and inhibit cytoplasmic protein translation, ultimately resulting in neurotoxicity. Importantly, TDP43 S-acylation is decreased in the familial ALS-associated TDP43 mutants as well as in SOD1-G93A mice and C9orf72-ALS induced pluripotent stem cell (iPSC)-derived neurons, suggesting the widespread involvement of TDP43 S-acylation in ALS pathogenesis. Our findings reveal an undescribed modification of TDP43 and provide deeper insight into the regulation of TDP43 pathological condensation in ALS.

St. Jude Children's Research Hospital

The purpose of this study is to investigate mobilization and collection of HSPCs in patients with bone marrow failure syndromes (BMFS) using granulocyte-colony stimulating factor (otherwise known as Filgrastim) with plerixafor to demonstrate safety and feasibility of collecting HSPCs to advance gene therapy. Primary objective: \- To characterize the safety of Filgrastim plus plerixafor in participants with bone marrow failure syndromes as determined by the incidence of adverse events (AEs). Secondary Objectives: * To characterize the feasibility of HSPC mobilization using Filgrastim plus plerixafor as determined by peripheral blood CD34+ counts. * To measure the mobilization effects of Filgrastim plus plerixafor in the peripheral blood in participants as determined by peak peripheral blood CD34+ counts. * To estimate efficacy of Filgrastim plus plerixafor for HSPC mobilization and apheresis collection in participants as determined by the yield of CD34+ cells (CD34+ cells/kg). Phase: PHASE1 Status: NOT_YET_RECRUITING Conditions: Bone Marrow Failure Syndrome Interventions: Filgrastim; Plerixafor; Leukapheresis

Manyu Zhu, Xin Xing, Zhao Li et al.

Chronic tendinopathy is typified by persistent tendon-associated pain, transmitted by local nociceptive neurons. However, the regulatory function of somatosensory neurons in the development of tendinopathy is unknown. Here, we show that sensory neurons grow into the tendon proper across preclinical models of chronic tendinopathy to serve a protective function against tendinopathic changes through interactions with resident tenocytes and infiltrating macrophages. Retrograde neuronal tracing combined with single-cell RNA sequencing (scRNA-seq) of dorsal root ganglion neurons revealed a tendon-specific innervation profile, including calcitonin gene–related peptide (CGRP)–positive nociceptors among other sensory neuron types. We further evaluated these findings in three complementary surgical and transgenic mouse models of disrupted sensory nerve growth. Conditional deletion of nerve growth factor ( Ngf ) in macrophages ( Ngf Csfr1 ) or inactivation of its high-affinity receptor, tropomyosin receptor kinase A (TrkA), on sensory neurons exacerbated tendinopathic changes. Subsequently, a “sensory-only” sural nerve denervation model phenocopied these results, including heightened macrophage infiltration and tenocyte apoptosis. scRNA-seq of tendinous tissue identified defective tenocyte differentiation and altered macrophage migration and polarization with tendon denervation. Last, neuron-tendon interaction analyses implicated neuron-derived fibroblast growth factor 1 (FGF1) as a preventative factor for tendon degeneration, a finding supported by tendon organ culture and in vivo assessment. Consistent with a conserved mechanism, human tendinopathy specimens showed FGF1 immunoreactivity associated with tendon-innervating nerve fibers. Collectively, our findings demonstrate that peripheral afferent neural networks exert a protective effect in preclinical tendinopathy models by secreting FGF1 and that targeting this pathway may offer therapeutic strategies to prevent tendinopathic changes.

Zhe Zhao, Jie Wang, Xuan Xiong et al.

William T. Maich, Muhammad Vaseem Shaikh, Anish Puri et al.

Glioblastoma (GBM) comprises nearly 15% of primary central nervous system (CNS) tumors and 50% of malignant primary CNS tumors worldwide. Considerable tumoral heterogeneity exists in GBM, leading to inefficacy of current treatments and the absence of meaningful improvements in frontline therapies in the past 20 years. Through multiomic analysis of patient-derived primary and recurrent GBM cell lines, we identified the urokinase plasminogen activator receptor (uPAR) as a protumorigenic marker of putative brain tumor–initiating cells and a potential therapeutic target. We found that genetic disruption of uPAR expression impaired protumorigenic characteristics in vitro and in vivo, highlighting its biological role in tumorigenesis. We then generated uPAR-specific chimeric antigen receptor (CAR) T cells, which demonstrated potent antitumor activity in recurrent GBM patient–derived xenograft models. In addition to direct tumor cell killing, we found that uPAR is expressed on GBM-associated macrophages, enabling uPAR CAR T cells to target both GBM itself and cells in the tumor microenvironment. Together, these data illustrate the potency and therapeutic potential of targeting uPAR in GBM.

Jana Bilanovic, Juliana Bortolatto, Susu Duan et al.

Abstract Transgenic mouse models expressing predefined T-cell receptors (TCRs) have been instrumental in advancing our understanding of T-cell biology. However, these traditional models rely on random genomic insertion of large constructs, require labor-intensive embryo manipulation, and frequently result in aberrant TCR expression and phenotypes. These limitations render traditional models insufficient to meet the mounting demands for rapid and precise model systems to evaluate TCR specificities. In this study, we developed a streamlined method that uses adeno-associated virus (AAV) and CRISPR/Cas9-mediated genome editing to precisely integrate pre-rearranged TCRα/β sequences into the mouse TCRβ ( Trb ) locus, enabling the rapid generation of TCR knock-in mice with physiological TCR expression and functional T-cell differentiation upon antigenic challenge. This approach bypasses the need for screening multiple founders for faithful TCR expression, enhancing the versatility and utility of monoclonal TCR mice in basic immunology and preclinical research, such as in the fields of cancer immunotherapy and vaccine development.

National Cancer Institute (NCI)

Background: Acute lymphoblastic leukemia (ALL) is a type of blood cancer. Chimeric antigen receptor (CAR) therapy involves taking immune cells (T cells) from a person and modifying them to better target cancer cells. CAR T-cell therapy that targets a marker called CD19 has been show to can cure ALL in many children and adults. But in about 50% of patients, the ALL comes back within a year. Researchers want to find out if a second treatment with CAR T-cell therapy that targets a different marker, CD22, can keep the cancer away longer. Objective: To see if CD22 CAR T-cell therapy can keep ALL away longer. Eligibility: People aged 3 to 65 years who have no signs of cancer after CD19 CAR T-cell treatment for ALL. Design: Participants will be screened. They will have imaging scans and tests of their heart function. A sample of tissue (biopsy) will be collected from their bone marrow. They will have a fluid sample collected from the area around their spinal cord. Participants will undergo collection of their white blood cells (T cells) during a procedure called leukapheresis. Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The cells will be altered in a lab to create CD22 CAR T-cell therapy. Participants will take drugs over 4 consecutive days to prepare their body for the CAR T-cell therapy; then they will receive their modified T cells through a tube inserted into a vein. Some people may need to stay in the hospital during treatment. Participants will have follow-up visits for 2 years. Phase: PHASE2 Status: RECRUITING Conditions: Acute Lymphoblastic Leukemia; B-All Interventions: CD22 CAR-transduced T cells; Cyclophosphamide; Fludarabine

Washington University School of Medicine

Diffuse large B-cell lymphoma is the most commonly occurring subtype of non-Hodgkin lymphoma, but treatment is often not curative, with as many as 50% of patients with adverse risk factors developing relapsed/refractory disease. CAR T-cell therapy has revolutionized modern cancer therapy, with axicabtagene ciloleucel and lisocabtagene maraleucel (anti-CD19 CAR T-cell therapies) FDA approved for second- or later-line treatment of relapsed/refractory large B-cell lymphoma. IL-7 plays a crucial role in T-cell homeostasis by inducing thymic differentiation, peripheral expansion, and extrathymic differentiation. It is the main regulator of T-cell hemostasis, inducing T-cell growth and proliferation in lymphopenic patients. There is data that suggests that exposure of T-cells to IL-7 may expand T-cells, prevent T-cell exhaustion, and improve effector functions. NT-I7 is a long-acting human IL-7 cytokine which has been shown in nonclinical studies to increase peripheral T-cells, antitumor efficacy, and tumor infiltrating lymphocytes, either as a monotherapy or in combination with chemo/radiotherapy and/or immune checkpoint inhibitors and CAR T therapy. This study is testing the hypothesis that the administration of NT-I7 following standard of care (SOC) approved CD19 CAR T-cell therapies for subjects with relapsed/refractory large B-cell lymphoma (LBCL) will be safe and tolerable and may increase the expansion and persistence of CAR T-cells in vivo, which may result in increased tumor response rate and improved clinical outcomes. Phase: PHASE1 Status: RECRUITING Conditions: Large B-cell Lymphoma Interventions: NT-I7; CAR T-cell therapy

Qifeng Deng, Jiru Liu, Jian Shen et al.

Acute severe ulcerative colitis (ASUC) now imposes an increasing global burden, yet lacks broadly effective therapeutic options. While organoid transplantation represents a promising approach for intestinal injuries, its efficacy for ASUC treatment remains suboptimal. Here, we elucidate the intrinsic mechanism of RIPK1 involvement in necroptosis initiation, and further develop an organoid-based dual-axis therapeutic paradigm for ASUC. We identified that RIPK1 undergoes PIAS1-catalyzed SUMO1 modification at lysine 305, which promotes its compartmentalization within phase-separated structures, thereby serving as nucleation platforms for accelerating RIPK3 amyloid fibril assembly. Interfering with phase separation of RIPK1 suppresses necroptosis in intestinal cells and colonic organoids in vitro, as well as alleviates intestinal injury and reduces mortality in vivo. Notably, while colonic organoid transplantation showed limited therapeutic efficacy in ASUC, a synergistic therapy combining necroptosis blockade and organoid transplantation effectively reduced inflammatory damage and enhanced epithelial regeneration by reprogramming the intestinal microenvironment. These findings suggest that the SUMO1-RIPK1 axis functions as a druggable checkpoint governing necroptotic cell fate and presents a clinically actionable strategy to potentiate regenerative medicine paradigms in ASUC pathogenesis.

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

This is a single-arm, open-label, single-center, dose-escalation Phase I platform study designed to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of an in vivo CAR-T therapy (V001 Injection, targeting BCMA, GPRC5D, DLL3,FcRH5, etc.) in patients with advanced malignant tumors. Phase: EARLY_PHASE1 Status: RECRUITING Conditions: Advanced Malignant Tumours Interventions: V001-BCMA; V001-GPRC5D; V001-DLL3; V001-FcRH5

Institute of Hematology & Blood Diseases Hospital, China

The aim of this study is to analyze the safety of BAFF-R Chimeric Antigen Receptor T-Cell Injection (BAFF-R CAR-T) in participants with relapsed/refractory BAFF-R-positive B-cell lymphoma and explore the Maximum Tolerated Dose (MTD). The secondary objective of this study is to explore the efficacy of BAFF-R CAR-T in participants with relapsed/refractory BAFF-R-positive B-cell lymphoma. The study also aims to explore the pharmacokinetic characteristics of BAFF-R CAR-T in vivo and the impact of BAFF-R CAR-T on lymphocyte subsets in vivo. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: DLBCL; CLL; FL; MCL; WM; MZL Interventions: BAFF-R CAR-T

Chenyan Huang, Amanda Sun, Jojo Reyes et al.

Mammalian reproduction requires substantial immune adaptations to safeguard reproductive success and to ultimately shape the evolutionary trajectories of a species. Systemic and placental immunity shift towards tolerance during pregnancy1,2; however, how maternal immunity adapts in barrier tissues-which are sites of frequent infection and inflammation-from pregnancy until the postpartum lactation period remains poorly understood. Here we report a previously unrecognized role for eosinophils, a type of granulocyte typically associated with allergies and helminth infections3,4, in remodelling the intestinal barrier during reproduction. Beginning in pregnancy and peaking during lactation, eosinophils accumulate in the small intestine in the absence of infection or inflammation. Using genetic and pharmacological perturbations, organoid cultures and single-cell and spatial transcriptomics, we show that eosinophils promote goblet cell differentiation in a stem-cell-intrinsic manner that leads to increased mucus production. This remodelling culminates during lactation and limits pathogen entry and dissemination to confer broad innate protection against enteric bacterial infections. Moreover, in mice, intestinal remodelling and innate defence persist weeks after lactation cessation. Our findings demonstrate that despite a general trend towards systemic immune modulation during reproduction, the maternal intestine undergoes remodelling to strengthen innate defence, a mechanism that may have evolved to protect mothers and offspring in pathogen-rich environments. More broadly, we establish a framework for studying tissue-specific immune adaptation across the reproductive cycle and highlight that tissues can retain changes following physiological reproduction, with lasting implications for host defence and women's health.

Shanghai Mental Health Center

This is an open-label, single-center, phase I clinical study in patients with moderate-to-severe early-onset Alzheimer's disease. The study aims to evaluate the safety, tolerability, and preliminary efficacy of neural stem cell-derived exosomes (NSC-EVs) administered by the intranasal route. A total of 9 participants will be enrolled in 3 frequency-escalation groups: once every 3 days, once every other day, and once daily, each for 28 days. Participants will undergo screening and baseline assessment, a 28-day treatment period, and follow-up visits at 4, 8, and 24 weeks after the end of treatment. Phase: PHASE1 Status: NOT_YET_RECRUITING Conditions: Alzheimer Disease (AD) Interventions: Neural Stem Cell-Derived Exosomes

Adia Med of Winter Park LLC

The goal of this clinical trial is to learn whether a new regenerative treatment called AdiaVita, made from umbilical cord blood-derived stem cells and exosomes combined with glutathione, is safe and can help improve kidney function in adults with chronic kidney disease (CKD). In this condition, the kidneys gradually lose their ability to filter blood as well as they should. The main questions it aims to answer are whether AdiaVita plus glutathione improves kidney function better than control treatments, as measured by blood tests for estimated glomerular filtration rate (eGFR) and creatinine levels, and whether the treatment is safe with acceptable side effects. Researchers will compare three groups. One group will receive AdiaVita plus glutathione. A second group will receive glutathione plus a placebo for AdiaVita. The third group will receive placebos for both treatments. A placebo looks like the real treatment but contains no active ingredients. This will help determine if the full treatment works better than the controls. Approximately 100 adults aged 18 to 80 with stage 2 to 4 chronic kidney disease may participate. Participants will be randomly assigned to one of the three treatment groups. They will receive monthly intravenous infusions at the clinic for the first three months and apply a skin spray twice daily at home during that period. The study lasts 12 months total for each participant, with regular visits for blood tests, physical exams, and safety monitoring. Certain participants in the control groups may switch to the active AdiaVita treatment after three months if they meet safety criteria. This is a single-blind study, meaning participants will not know which treatment they receive. Participant safety is closely monitored by the research team and an independent board throughout the study. Phase: PHASE1 Status: RECRUITING Conditions: Chronic Kidney Disease; Kidney Disease; Kidney Disease, Chronic; Chronic Kidney Disease (CKD); CKD Interventions: Umbilical Cord Blood-Derived Stem Cells and Exosomes; Glutathione IV; Glutathione Spray; Placebo IV; Placebo Glutathione IV; Placebo Spray

Allogene Therapeutics

The purpose of the UNIVERSAL study is to assess the safety, efficacy, cell kinetics, and immunogenicity of ALLO-715 with or without Nirogacestat in adults with relapsed or refractory multiple myeloma after a lymphodepletion regimen of ALLO-647 in combination with fludarabine and/or cyclophosphamide, or ALLO-647 alone. Phase: PHASE1 Status: COMPLETED Conditions: Relapsed/Refractory Multiple Myeloma Interventions: ALLO-715; ALLO-647; Fludarabine; Cyclophosphamide; Nirogacestat

Institute of Hematology & Blood Diseases Hospital, China

This is a prospective, open-label, non-randomized cohort study evaluating the efficacy and safety of a pediatric-inspired chemotherapy regimen (IH-2014 based) combined with venetoclax and immunotherapy in adult patients with newly diagnosed Ph-negative Acute Lymphoblastic Leukemia (ALL). Patients aged ≥14years,≤60 years will be enrolled. Treatment includes induction, consolidation, early intensification, delayed intensification, and maintenance phases. The use and number of cycles of immunotherapy will be based on patient preference. The primary endpoint is Event-Free Survival (EFS) and MRD-negative CR rates after induction therapy(by flow cytometry and NGS). Secondary endpoints include Complete Remission (CR) rate, MRD-negative CR rates at 12 weeks (by flow cytometry and NGS), Overall Survival (OS), Relapse-Free Survival (RFS), and cumulative relapse rate. Phase: NA Status: RECRUITING Conditions: Acute Lymphoblastic Leukemia, Adult Interventions: VDCLP+V; 2VIP; Consolidation Therapy; Maintenance Therapy; Blinatumomab; Venetoclax; CNS Prophylaxis; CAR-T Cell Therapy; Hematopoietic Stem Cell Transplantation (HSCT)

Sapna Vyas

Recent advances have shown that cells from human blood, skin and urine samples can be reprogrammed to become stem cells. These are called induced Pluripotent Stem Cells (iPSCs) and share many characteristics with embryonic stem cells, including an unlimited capacity for proliferation and the potential to become any cell in the body. Beneficially, the use of iPSCs avoids the ethical difficulties which surround embryonic stem cells and allows generation of iPSC lines which are disease representative. For example, we could take skin samples from an individual diagnosed with Huntington's disease and their unaffected sibling and using this technology, generate iPSC lines from both individuals. Using these iPSCs, we could produce disease affected cell populations from the affected and unaffected individuals, use these cells to research why specific cell populations are affected by disease and test new treatments to combat disease progression, essentially producing a 'disease in a dish'. This is just one example of many for which this technology could be applied. We can also utilise gene-editing techniques to generate isogenic controls or insert disease related mutations to assess disease phenotype. Although generation of iPSC lines has been robustly proven across multiple disease backgrounds, many aspects of their downstream use still remain to be determined. Particularly, robust protocols for directing iPSCs towards cell fates such as neurons or blood cells must be developed to fully realise application of iPSCs in disease modelling and drug screening. This study involves the collection of human blood, skin or urine samples from subjects bearing a range of genetic diseases alongside those from individuals who have not been diagnosed with a disease, as controls. These samples will be used to generate iPSC lines for development of differentiation and disease phenotyping protocols. Status: RECRUITING Conditions: Genetic Disease Interventions: Skin biopsy/Urine Collection/Blood Sample Collection

Institute of Hematology & Blood Diseases Hospital, China

This is a prospective, open-label, single-arm clinical trial evaluating a treatment strategy for previously untreated Mantle Cell Lymphoma (MCL). The study will enroll patients who have not received prior systemic therapy for MCL. All patients will receive the ZGR induction regimen. Risk-adapted maintenance therapy will be applied: non-high-risk patients will receive lenalidomide and zanubrutinib maintenance for 1 and 2 years, respectively; high-risk patients will undergo CAR-T cell therapy followed by the same maintenance regimen. The primary objective is to assess the feasibility and preliminary efficacy of this treatment approach in the first-line setting of MCL. Phase: PHASE2 Status: RECRUITING Conditions: Mantle Cell Lymphoma Interventions: Zanubrutinib; Obinutuzumab; Lenalidomide; CAR-T Cell Therapy

Shenzhen University General Hospital

1. Study Title: A Study on the Efficacy and safety of Autocrine p40-Expressing CD19-Targeted Chimeric Antigen Receptor T Cells (CD19-CAR.p40-T) in Patients With Relapsed/Refractory CD19-Positive Hematologic Malignancies 2. Study Objectives: 2.1.1 Primary Objective To evaluate the safety of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies. 2.1.2 Secondary Objective To evaluate the efficacy of autocrine p40-expressing CD19-targeted chimeric antigen receptor T cells (CD19-CAR.p40-T) in the treatment of patients with relapsed/refractory CD19-positive hematologic malignancies. 2.1.3 Exploratory Objective To evaluate the in vivo expansion and persistence of CD19-CAR.p40-T cells. 3. Participant Intervention: Participants will receive lymphodepleting chemotherapy (FC regimen: Fludarabine + Cyclophosphamide) on Days -5, -4, and -3 relative to the planned CD19-CAR.p40-T cell infusion. The CD19-CAR.p40-T cell infusion will be administered 72 hours after the completion of the FC chemotherapy. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B Cell Lymphoma; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia Interventions: CAR-T cell

Zhuoran Xu, Hui-Qi Qu, Joe Chan et al.

Recent advances in long-read single-cell transcriptome sequencing (lr-scRNA-Seq) enable full-length isoform profiling at single-cell resolution. We present SCOTCH (Single-Cell Omics for Transcriptome CHaracterization), an end-to-end, platform-independent pipeline for isoform characterization from lr-scRNA-Seq data, supporting Nanopore and PacBio sequencing as well as 10X Genomics and Parse Biosciences protocols. SCOTCH models isoforms as combinations of non-overlapping sub-exons and applies dynamic thresholding for robust isoform assignment while efficiently address ambiguous mapping issues. By refining sub-exon boundaries through integration of read coverage with existing annotations and applying an iterative clustering strategy to reconstruct novel transcripts, SCOTCH reliably recovers more true novel isoforms than existing splice-graph-based methods, with poly(A)-aware filtering further reducing false-positive structures. Extensive simulations demonstrate improved quantification of known isoforms and enhanced reconstruction of novel isoforms. Analyses of human blood and cerebral organoid datasets across multiple platforms further confirm SCOTCH's ability to resolve cell-type-specific transcriptome profiles and uncover experimentally supported novel isoforms.

John F. DiPersio, Guenther Koehne, Nirali N. Shah et al.

Wugen, Inc.

The T-RRex study evaluates the efficacy of WU-CART-007 for patients with Relapsed/Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL)/Lymphoblastic Lymphoma (LBL) and to WU-CART-007 as a therapy to induce complete Minimum Residual Disease (MRD) negative response Phase: PHASE2 Status: RECRUITING Conditions: T-cell Acute Lymphoblastic Leukemia; Lymphoblastic Lymphoma Interventions: WU-CART-007

Soochow University

This clinical trial aims to evaluate the use of a handheld Magnetic Particle Imaging (MPI) device for real-time, non-invasive monitoring of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in patients with knee osteoarthritis (OA). The primary objective is to visualize and quantify the distribution, retention, and survival of SPIO (superparamagnetic iron oxide)-labeled MSCs within the joint space following intra-articular injection. By correlating MPI signal dynamics with established clinical outcomes (e.g., WOMAC, VAS scores) and anatomical MRI assessments, the study seeks to predict treatment efficacy and optimize therapeutic strategies for OA. Current assessment of MSC therapy relies largely on MRI for structural evaluation, which has limited sensitivity for tracking early cell viability and migration. MPI offers high-contrast, radiation-free functional imaging capable of directly detecting SPIO-labeled cells. This study will enroll patients with mild-to-moderate OA (Kellgren-Lawrence grade II-III). Participants will receive a single injection of ferumoxytol-labeled UC-MSCs into the affected knee. MPI scans will be performed at multiple timepoints (day 1, 3, 7, and 30) to monitor cell homing, retention rate, and signal decay. MRI will be used in parallel to evaluate cartilage morphology and synovial changes. The study expects to demonstrate that MPI can effectively track MSC behavior in vivo, providing a novel tool to understand cell therapy mechanisms, assess treatment response early, and potentially guide personalized OA management. Phase: EARLY_PHASE1 Status: ENROLLING_BY_INVITATION Conditions: Knee Arthritis Osteoarthritis Interventions: Human Umbilical Cord-derived Mesenchymal Stromal Cells (hUC-MSCs); Ferumoxytol (SPIO) Solution for Injection (Placebo)

National Cancer Institute (NCI)

Background: People who have had an allogeneic hematopoietic stem cell transplant (HCT) have bone marrow or an immune system that is damaged. They get stem cells from a donor who is a relative. Researchers want to study stem cell donors and recipients to learn about the long-term effects of HCT. They want to learn how the stem cells change and how to improve their ability to fight cancer. Objective: To provide long-term follow-up care for people who underwent or will undergo HCT. To collect data, blood, and tissue samples to learn about late complications after HCT. Eligibility: Adults age 18 and older who will undergo HCT or underwent HCT and are surviving one year or more from the date of HCT. The stem cell donors for these recipients are also needed. Design: Recipients will have 1 visit each year. They will have a physical exam. They will answer questions about their medical history and health. They will receive screening and surveillance testing. They will complete brief questionnaires. Recipients will have blood tests. They may have tissue biopsies or specimens (such as tissue in their cheek or skin or bone marrow biopsy). Recipients will give their current address and phone number, and the same data for one or two other people, who can get in contact with them. After the first visit at the clinic, some recipients may see a doctor close to home to get the necessary information and send it to NIH. Donors will come to the clinic for 1 visit. They will answer questions about their medical history. Blood samples will be taken. Status: RECRUITING Conditions: Hematopoietic Stem Cell Transplantation; Tissue Donors

University of Dublin, Trinity College

A prospective, longitudinal cohort study will be conducted to evaluate the effects of treatment on the physical function of patients undergoing Allogeneic Hematopoeitic Stem Cell Transplant. Status: NOT_YET_RECRUITING Conditions: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)

University Hospital, Montpellier

The aim of this interventional, cross-sectional and pathophysiological experimental study is to evaluate the potential of a patient's induced pluripotent stem (iPS) cells, used prior to the re-differentiation stage, to enable ex vivo repair of the injured epithelium in patients with chronic obstructive pulmonary disease (COPD), smokers without COPD and non-smoking controls. The main questions it aims to answer are: * to evaluate the repair capacity of bronchial epithelium in COPD subjects, using a model of bronchial epithelium reconstituted in air/liquid interface culture and the iPS model. * epithelia repair capacities in normal or aberrant situations, as well as the time required for this repair, and to determine the involvement of grafted iPS cells in epithelia repair in cultured control subjects, smokers without COPD and COPD patients. Researchers will compare 3 groups of participants (COPD patients, smokers without COPD and non-smokers without COPD) for epithelial repair efficacy between non-grafted ALI cultures and ALI cultures grafted with iPS cells, in order to assess their contribution to epithelial repair. Participants will undergo a bronchial fibroscopy (for clinical indications) with two additional biopsies specific to the study. This research could lead to breakthroughs in cell-based therapies for COPD, with long-term implications for epigenetic treatments and in vivo applications. Phase: NA Status: RECRUITING Conditions: Pulmonary Disease, Chronic Obstructive Interventions: bronchial fibroscopy

Rinri Therapeutics

Rinri Therapeutics is conducting a clinical trial of a new cell therapy called Rincell-1. Rincell-1 is being developed to treat adults with neural hearing loss, either age related hearing loss or auditory neuropathy, who also meet criteria for a cochlear implant. The goals of this study are: * To learn about the safety profile of Rincell-1, the procedure used to inject it and the medications given to promote the growth of the cells * To evaluate how well Rincell-1 works by measuring changes in the function of auditory neurons. * To understand if Rincell-1 can be easily and successfully given at the same time as cochlear implant surgery Participants will be randomly assigned to one of two groups: one group that receives a standard care cochlear implant, and the other that will receive an injection of Rincell-1 at the same time as their standard care cochlear implant. Researchers will compare the safety of Rincell-1 in combination with a cochlear implant to a cochlear implant on its own. Participants will take part in the trial for 52 weeks after CI surgery. During that time, they will have regular follow-ups and will take daily measurements at home of their hearing health. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Sensorineural Hearing Loss; Presbyacusis; Auditory Neuropathy Interventions: Otic neural progenitors; cochlear implantation

Olena Zhulyn, Vanessa Donega

Compared to amphibians, fish, and reptiles, mammals have an impaired capacity to regenerate the brain, despite the presence of a neural stem cell pool. Here, we consider the biological significance of a stem cell source in the human brain by exploring evolutionary trade-offs that may guide retention of regenerative capacity in mammals and the risks and benefits of active neurogenesis in adults. We discuss whether reduced regenerative capacity in humans is adaptive or stochastic and examine the role of the injured and diseased brain environment in preventing efficient brain repair. We discuss the therapeutic potential of activating the latent regenerative potential of the human brain to reverse tissue damage or degeneration and whether this approach carries with it an unanticipated risk of cancer.

Shuzhe Xiao, Lingling Wang, Xu Li et al.

Abstract Recent research has shown that extracellular vesicles (EVs) have significant potential in treating lung injuries. These vesicles facilitate communication between cells and regulate important biological processes, including cell growth, blood vessel formation, and inflammatory responses. Due to their natural ability to cross biological barriers and low risk of immune rejection, EVs are potential vehicles for targeted drug delivery. Among various biological sources, umbilical cord-derived EVs are highly advantageous because the collection process is non-invasive and provides a high yield of vesicles. Preclinical studies have demonstrated their therapeutic potential in conditions such as bronchopulmonary dysplasia, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and asthma. This review summarizes the current evidence supporting the use of umbilical cord-derived EVs for lung diseases. It also discusses key translational challenges, such as manufacturing scalability and product consistency, alongside advanced engineering strategies for future clinical use.

City of Hope Medical Center

This is a study to evaluate the safety and toxicity of a treatment regimen consisting of 2 cycles of pre-transplant immunosuppressive therapy followed by myeloablative preparative regimen and allogeneic hematopoietic stem cell transplantation from a haploidentical donor in patients with sickle cell disease. The overall goal of this study is to expand the donor pool for hematopoietic stem cell transplantation in sickle cell disease using haploidentical donors, and to develop a non-toxic, myeloablative regimen, with the goal of achieving a consistent donor chimerism utilizing pre-transplant immunosuppressive therapy. Phase: PHASE1 Status: RECRUITING Conditions: Sickle Cell Disease Interventions: Hematopoietic stem cell transplantation

Kang Stem Biotech Co., Ltd.

Long-Term Follow-up Study of Subjects With Moderate to Severe Chronic Atopic Dermatitis Who Had Administered FURESTEM-AD Inj. in K0106 Study Status: ACTIVE_NOT_RECRUITING Conditions: Dermatitis, Atopic

National Institute of Allergy and Infectious Diseases (NIAID)

Idiopathic CD4 lymphocytopenia (ICL) is a rare syndrome defined by consistently low CD4 T cell counts (\<300/mm3) without evidence of HIV infection or other known immunodeficiency. Patients with ICL are at risk for opportunistic infections typically associated with HIV/AIDS such as disseminated cryptococcal infection and severe human papillomavirus-related dysplasia. More than 20 years since the description of ICL, its etiology, pathogenesis, and management remain unclear. In this study we propose to administer the combination of granulocyte colony stimulating factor (G-CSF) and plerixafor to ICL patients and healthy volunteers with the objective of harvesting mobilized CD34+ hematopoietic progenitor cells (HPCs) by apheresis for transfer into immunocompromised mice and for study with in vitro assays. The mice studies would serve to investigate thymic development, survival, and trafficking of the mobilized human cells within murine lymphoid and non-lymphoid organs. HPCs are used for various therapies and there is an increasing use of agents that stimulate the bone marrow to produce progenitor cells and move them into the bloodstream where they may be harvested by apheresis. Not all patients respond to GCSF with vigorous HPC mobilization. The binding of chemokine receptor CXCR4 to stromal cell derived factor (SDF-1 or CXCL12) is an important interaction between a hematopoietic progenitor cell and its marrow environment. Plerixafor is a CXCR4 inhibitor which blocks binding to SDF-1 resulting in the release of hematopoietic progenitor cells (CD34+) into peripheral circulation. In pharmacodynamic studies of plerixafor in conjunction with G-CSF compared to G-CSF and placebo, a two-fold increase in CD34+ cell count was observed. Due to the important role CXCR4 plays in immune cell trafficking and its potential role in the pathogenesis of ICL, we propose as a secondary objective to assess peripheral CD4 T cell and CD34+ hematopoietic progenitor cell numbers and functions in ICL patients compared to controls following G-CSF and plerixafor administration. Study participants will be screened within 12 weeks prior to the study period. Eligible participants will receive G-CSF for 5 days with hospitalization on Day 4 for plerixafor injection followed by apheresis on Day 5. Participants will return for examinations and blood draws on Days 8 and 12. Phase: PHASE2 Status: RECRUITING Conditions: Idiopathic CD4-Positive; T-Lymphocytopenia Interventions: Filgrastim; Plerixafor

Marcela V. Maus, M.D.,Ph.D.

This research study involves the study of TriPRIL CAR T Cells for treating people with relapsed or refractory multiple myeloma and to understand the side effects when treated with TriPRIL CAR T Cells. This research study involves the study drugs:. * TriPRIL CAR T Cells * Fludarabine and Cyclophosphamide: Standardly used chemotherapy drugs as part of lymphodepleting process Phase: PHASE1 Status: RECRUITING Conditions: Multiple Myeloma; Multiple Myeloma in Relapse; Refractory Multiple Myeloma Interventions: TriPRIL CAR T Cells; Cyclophosphamide; Fludarabine

Azienda USL Reggio Emilia - IRCCS

This is a feasibility study to implement a Survivorship Care (SC) Plan for patients with hematologic cancer undergoing hematopoietic stem cell transplantation (HSCT). The study evaluates if the intervention is feasible within the Italian national health system, focusing on retention rates, quality of life, unmet needs and caregiver burden Phase: NA Status: NOT_YET_RECRUITING Conditions: Hematologic Neoplasm; Hematopoietic Stem Cell Transplantation; Survivorship; Cancer Survivorship Interventions: Survivorship Care (SC) Plan

Xinyuan Pan, Lan Yang, Jinqi Zou et al.

Mona M. Khaled, Asmaa M. Ibrahium, Ahmed I. Abdelgalil et al.

Francisco Algaba Chueca

Endometriosis is a chronic inflammatory condition characterized by the presence of endometrium-like tissue outside the uterine cavity. It is estimated to affect approximately 10% of women of reproductive age and it is associated with chronic pelvic pain and infertility, among other symptoms. Endometriosis involves complex changes in the body's cells and immune response. For this reason, the goal of this observational study is to characterize the functional, molecular, and immunological alterations in menstrual blood-derived stem cells (MenSCs) and differentiated decidual stromal cells in women with endometriosis; to validate these findings in endometrial tissue and endometriomas; and to establish their correlation with clinical parameters, with the aim of identifying key pathogenic mechanisms and potential therapeutic targets. The main questions it aims to answer are: * Are there functional and molecular changes in MenSCs from patients with endometriosis compared to healthy volunteers? * Are there any variations in the immune properties of MenSCs throughout the menstrual bleeding period in patients with endometriosis compared to healthy volunteers? * Are these changes also present in endometrial tissue and endometrioma samples? * Can these changes be correlated with clinical parameters in patients with endometriosis? * Can MenSCs serve as a potential therapeutic target for endometriosis? Some participants will be asked to provide menstrual blood on a single day, while others will provide samples during the first five days of menstruation. Additionally, all participants will answer questionnaires about their diet, physical activity, stress, and pain levels. Therefore, the study does not involve the evaluation of a specific intervention on the participants. The results will enable the identification of key altered mechanisms and potential therapeutic targets, thereby contributing to the development of more effective strategies for the diagnosis and treatment of the disease. Status: RECRUITING Conditions: Endometriosis Interventions: Menstrual blood-derived stem cells collection and in vitro characterization

Shanghai Life Science & Technology

A pilot study to evaluate the safety and feasibility of umbilical cord mesenchymal stem cells in the treatment of acute myocardial infarction by catheter transplantation Phase: PHASE1 Status: WITHDRAWN Conditions: Left Ventricular Dysfunction; Acute Myocardial Infarction Interventions: UC-MSC; Control Group

Ponthip Pratumkaew, Methichit Wattanapanitch, Vip Viprakasit et al.

Transfusion-dependent hemolytic anemia caused by compound heterozygosity due to mutations in the erythroid Kr&#xfc;ppel-like factor 1 (KLF1) gene is a rare and severe blood disorder. The clinical manifestations of the patient are mainly related to erythroid cells. Moreover, the roles of the identified KLF1 mutations in the pathophysiology of this disease remain unclear due to the lack of an appropriate study model. The advent of genome editing technology combined with the generation of patient-specific induced pluripotent stem cells (iPSCs) may provide a better understanding of the molecular mechanisms underlying this disease in an in vitro system and offer a novel therapeutic approach in the future.

First Affiliated Hospital of Zhejiang University

This study aims to investigate the safety and preliminary efficacy of an innovative therapeutic strategy combining chidamide with NKG2D-directed chimeric antigen receptor natural killer (CAR-NK) cells in individuals living with HIV. The approach is predicated on the "shock and kill" paradigm: chidamide is employed to reactivate latent HIV reservoirs and upregulate surface target ligands (NKG2D ligands) on infected cells; subsequently, allogeneic NKG2D CAR-NK cells are infused to specifically recognize and eliminate these "marked" cells. This is a phase I, open-label, single-arm clinical trial comprising two distinct stages: a dose-escalation phase (phase Ia, utilizing a "1+3+3" design) and a dose-expansion phase (phase Ib). A total of 20 HIV-infected individuals who are stable on antiretroviral therapy (ART) and have suppressed plasma viremia are planned for enrollment. Participants will receive oral chidamide over approximately five weeks, followed by two cycles of intravenous CAR-NK cell infusion. The primary endpoint is the safety and tolerability of the regimen, with particular attention to immune-related adverse events including cytokine release syndrome (CRS). Secondary endpoints encompass exploratory assessments of potential virologic and immunologic effects, such as alterations in plasma HIV RNA, cell-associated viral nucleic acids, and CD4+ T-cell counts. This study is intended to provide initial human safety data and preliminary evidence regarding the potential of this combination strategy to contribute toward a functional cure for HIV infection. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: HIV (Human Immunodeficiency Virus) Interventions: Chidamide Combined with NKG2D CAR-NK Cell Therapy

iRegene Therapeutics Co., Ltd.

This is a phase 1/2 clinical study to evaluate the safety, tolerability, feasibility, and preliminary efficacy of NouvNeu001 in patients with advanced Parkinson's Disease. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Parkinson Disease Interventions: Human Dopaminergic Progenitor Cells

Brigham and Women's Hospital

The main purpose of this study is to determine if a tailored peer support intervention (STEPP-Care) is feasible among caregivers of patients undergoing hematopoietic stem cell transplantation (HSCT). Phase: NA Status: NOT_YET_RECRUITING Conditions: Hematopoietic Stem Cell Transplantation Interventions: STEPP-Care

City of Hope Medical Center

This trial studies the impact of a 12-month invention focused on early detection of skin cancer and timely follow up in patients who underwent stem cell transplant and their primary care providers. Some stem cell transplant survivors may develop complications related to the treatment they received. Many of these complications may not be known for years after the treatment and preventive measures can be taken to reduce the chances that a complication will occur and encourage early detection. This study focuses on one complication that stem cell transplant survivors are at high risk of developing - skin cancer. An early diagnosis of skin cancer is important since the cancer is usually smaller, requires less extensive treatments, and has better outcomes. Teaching skin self-examination and encouraging patients to alert doctors to skin changes may provide an important opportunity for early detection of skin cancer. Phase: NA Status: ACTIVE_NOT_RECRUITING Conditions: Skin Carcinoma Interventions: Computer-Assisted Intervention; Dermatoscope; Educational Intervention; Educational Intervention (Physician); Questionnaire Administration; Text Message

Shuangshuang Wang, Dexuan Zhuang, Dongyu Hou et al.

Psoriasis is driven by sustained epidermal inflammation tightly coupled to dysregulated redox homeostasis. Although current systemic therapies are effective, their long-term use is limited by safety concerns. Dental pulp stem cell-derived exosomes (DPSC-Exo) have emerged as promising immunomodulatory, cell-free therapeutics, yet their role in regulating epithelial redox-inflammatory balance remains undefined.

Guanghui Tan, Ao Zhang, Xuesha Cao et al.

Abstract The placenta is essential for fetal development, yet its molecular evolution across mammals remains elusive. Here, we present a comprehensive single-cell transcriptomic atlas of ~300,000 cells from ten species representing the four primary placental types: discoid, cotyledonary, diffuse, and zonary. Our cross-species analysis identifies trophoblast lineages as the primary drivers of placental diversification. By reconstructing differentiation trajectories, we elucidate the regulatory networks shaping trophoblast development across diverse architectures. We propose that the unique gene expression profile of human trophoblasts underlies the susceptibility to preeclampsia and miscarriage. Functional experiments demonstrate that TGIF1 acts as a key upstream regulator of extravillous trophoblast growth and migration. TGIF1 and its targets, including ADAM12 , WNT3A , and ZNF831 , are associated with preeclampsia and pregnancy loss. Collectively, this high-resolution framework provides fundamental insights into the molecular evolution of the placenta and its contribution to reproductive success and diseases.

Keyu Wang, Xiaoke Zeng, Yaoguang Zhang et al.

Ectomesenchymal stem cells (EMSCs) are critical for craniofacial bone development, and low-affinity nerve growth factor receptor (LNGFR) is closely associated with their stemness. However, the specific role of LNGFR in EMSC osteogenesis remains unclear. Here, we investigated this using Lngfr knockout (lngfr-/-) mice and demonstrated that lngfr-/-EMSCs exhibited decreased proliferation, migration, and osteogenic differentiation capacities in vitro. Furthermore, impaired skeletal development and reduced mineralization were observed in lngfr-/- fetal mice in vivo. Circular RNA (circRNA) sequencing identified the growth hormone (GH) pathway as a key factor involved in LNGFR-regulated osteogenesis of EMSCs. Co-immunoprecipitation (Co-IP) assays further confirmed the interaction between LNGFR and growth hormone receptor (GHR). lngfr-/-suppressed GHR expression and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation, leading to downregulation of the GH/insulin-like growth factor 1 (IGF-1) signaling pathway. Modulation of the JAK/STAT pathway affected osteogenesis, while exogenous GH rescued the osteogenic defects via the GHR/JAK-STAT/IGF-1 axis. Collectively, these findings demonstrated that LNGFR promoted EMSC osteogenesis by activating the GHR/JAK-STAT/GH-IGF-1 signaling axis, providing new insights into craniofacial development and regenerative medicine.

Hyun Su Park, Gwang-Bum Im, So Yun Jeong et al.

Low retention of transplanted stem cells at target sites remains a major barrier to the clinical translation of cell-based therapies. Conventional strategies, including genetic modification, chemical functionalization, and biomaterial encapsulation, often face limitations in translational feasibility, safety, or procedural complexity. Here, we present a nanoparticle-enabled biophysical approach to enhance cell retention. We incorporate cell-settling nanoparticles composed of clinically approved materials into mesenchymal stem cells, increasing cellular density to accelerate gravitational settling and improve adhesion and survival. Building on this, we develop copper-chaperone-activatable nanoparticles, which enhance tissue regeneration and anti-fibrotic signaling through activation of fibroblast growth factor 2 and a positive feedback loop. In a mouse skin wound model, we show that copper-chaperone-activatable nanoparticle-treated mesenchymal stem cells exhibit enhanced vascularization and reduced fibrosis. These findings demonstrate that modulation of cellular density and physical forces can improve stem cell engraftment, establishing a biophysical framework for safe and translationally relevant cell-based therapies.

Yuhang Shi, Zhengyi Ni, Fei Wang et al.

Osteoarthritis (OA) is a complex, multifactorial whole-joint disease characterized by progressive articular cartilage degeneration, synovitis, and subchondral bone remodeling. Current clinical interventions primarily offer symptomatic management but do not halt or reverse disease progression. Recent advancements in regenerative medicine have emphasized mesenchymal stromal cell (MSC) therapy owing to its substantial potential in tissue repair and microenvironmental modulation. This review systematically evaluates the therapeutic efficacy and potential mechanisms of bone marrow-derived MSCs, adipose-derived stromal cells, umbilical cord-derived MSCs, synovium-derived MSCs, embryonic stem cell-derived MSCs and induced pluripotent stem cell-derived MSCs, as well as MSC-derived exosomes, in modulating the joint microenvironment. Furthermore, we discuss recent innovations in nanotechnology-enhanced strategies, designed to improve targeting specificity and therapeutic durability of MSC-based interventions. This review aims to establish a foundational framework and translational roadmap for the development of next-generation disease-modifying therapies for OA.

David Avigan

This study is to evaluate the safety and effectiveness of dendritic cell DC/MM fusion vaccine in combination with standard of care B-cell maturation antigen (BCMA) CAR-T cell therapy in participants with relapsed/refractory multiple myeloma. The names of the study drugs involved in this study are: * DC/MM fusion vaccine (a type of personalized cancer vaccine) * Granulocyte-macrophage colony-stimulating factor (GM-CSF) (a type of growth factor or hormone) Phase: PHASE1 Status: RECRUITING Conditions: Multiple Myeloma; Refractory Multiple Myeloma; Relapse Multiple Myeloma Interventions: DC/MM Fusion Vaccine; GM-CSF

Assistance Publique Hopitaux De Marseille

This prospective study aimed to validate a new prognostic approach of endothelial progenitor cells associated biomarkers in patients with acute coronary syndromes . Recruitment is made prospectively by two centers of Inter -region South Mediterranean, Phase: NA Status: COMPLETED Conditions: Acute Coronary Syndromes Interventions: blood sample

Claudia Steiner

Chang Xu, Xue Lv, Shangda Yang et al.

Hematopoietic stem cells (HSCs) rely on specialized niche cells for maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. Here, we identified a subset of Procr+ endothelial cells (ECs) with progenitor-like properties in bone marrow (BM), which is critical for vascular homeostasis and injury regeneration. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr serves dual biological functions as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds HSPA8 to promote Foxc2 nuclear translocation, upregulating Dll4 transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC crosstalk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSCs Notch signaling, coordinating their adipogenic-osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ EPCs in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights Procr&#x207a; EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.

Ohman Kwon, Hana Lee, Jaeeun Jung et al.

Anna Pulawska-Czub, Alicja Olczak-Cossu, Tomasz D Pieczonka et al.

Abstract Rodent and primate digit tips exhibit a remarkable regenerative capacity following amputation, driven by highly proliferative nail stem cells (NSCs) with active canonical Wnt signaling. Recently, a distinct, slow-cycling population of bi-functional nail proximal fold stem cells (NPFSCs) has been identified, contributing to both peri-nail epidermis and nail plate (NP). Here, we demonstrate that NPFSCs actively participate in nail growth, orchestrating digit regeneration, with BMP signaling serving as a key regulator. Inhibition of BMP resulted in an epidermalized NP-like structure with limited regeneration due to impaired Wnt pathway activation in the nail matrix cells. Conversely, BMP activation enhanced NPFSCs’ involvement in the nail matrix and significantly promoted digit regeneration. We further revealed that enhanced BMP activity not only accelerated nail and bone regrowth but also extended the regenerative boundary proximally, enabling full regeneration after up to ∼60% removal of the distal phalanx (P3). Moreover, in BMP gain-of-function (GoF) models, extreme proximal amputation, removing the majority of the P3, still permitted partial NP regeneration despite the absence of bone reconstruction. Finally, we isolated and cultured lineage-traced NPFSCs and transplanted them into immunocompromised mice, where they integrated into the nail proximal fold and contributed to nail matrix progenitors during regeneration. Transplanted NPFSCs retained their regenerative capacity in vivo, highlighting their therapeutic potential. Collectively, our findings identify a pivotal role of BMP signaling in mediating NPFSC-driven digit regeneration, reveal BMP-Wnt cross-talk as essential to this process, and provide a framework for enhancing regenerative outcomes in previously non-regenerative contexts following traumatic amputation.

Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

The purpose of this study is to evaluate the efficacy, safety and drug levels of CC-97540 in participants with active systemic lupus erythematosus (SLE) including lupus nephritis with inadequate response to glucocorticoids and at least 2 immunosuppressants. Phase: PHASE2 Status: RECRUITING Conditions: Lupus Erythematosus, Systemic; Lupus Nephritis Interventions: CC-97540; Fludarabine; Cyclophosphamide

Chinese PLA General Hospital

The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from the ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients' peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the human leukocyte antigen (HLA)-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators' observed clinical safety data supported the notion that only genomic deletion of Power3 (SPPL3) gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response. In this study, investigators will disable the Power3 (SPPL3) gene of T cells from healthy donors to prepare CAR T cells (purified CAR-positive T cells \> 90%). This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL). Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Acute Lymphocytic Leukemia Interventions: TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell; Fludarabine; Cyclophosphamide

Karen Gr&#xfc;tz, Axel K&#xfc;nstner, Christin Krause et al.

The genetic mechanism underlying the neurodegenerative movement disorder X-linked dystonia-parkinsonism (XDP) involves a retrotransposon insertion within the TAF1 gene. TAF1 encodes the TATA-box binding protein-associated factor 1, the largest subunit of the basal transcription factor TFIID, which connects transcription activation to the assembly of the RNA polymerase II preinitiation complex at the core promoter of genes. This study investigated how the TAF1 mutation affects the transcriptomes of XDP patient-derived neurons under basal conditions and in response to mitochondrial toxins. Gene set enrichment analysis revealed that, under basal conditions, patient-derived neurons exhibited predominantly upregulated pathways compared to controls. However, exposure to mitochondrial toxins induced a global shift toward downregulation of pathways in XDP neurons, affecting genome maintenance, epigenetic regulation, adaptive neuronal function, and transcription. Our findings suggest that neurons from XDP patients are more susceptible to mitochondrial stress than controls, leading to widespread transcriptomic downregulation and increased DNA damage.

Elisa T Zhang

Menstruation entails repeated cycles of cyclical shedding and scarless regeneration of the endometrium, yet the precise cellular states underlying this process have remained poorly defined. In this issue, Nikolakopoulou et al. establish an in vitro menstrual cycle (IVMC) protocol using human endometrial organoids, revealing WNT7A as a central regulator of epithelial regeneration.

Liping Dou

This is a single-center, open-label, single-arm prospective study designed to evaluate the safety, tolerability, and efficacy of dual-target CD22/CD19 chimeric antigen receptor (CAR)-T cell therapy as consolidation treatment in patients with standard-risk B-cell acute lymphoblastic leukemia (B-ALL) in remission. Eligible patients will undergo leukapheresis for CAR-T cell manufacturing, followed by lymphodepleting chemotherapy and CAR-T cell infusion. Patients will be closely monitored for safety, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity, and infections. Efficacy endpoints include event-free survival (EFS), overall survival (OS), progression-free survival (PFS), relapse rate, and mortality. Exploratory analyses will assess CAR-T cell expansion kinetics and clonal evolution. The total follow-up duration is planned to be 2 years. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia Interventions: CD22/CD19 Dual-Target CAR-T Cells

Zhen Sun, Ludi Zhang, Lijian Hui

Hepatocyte-based therapies represent a promising alternative to liver transplantation, yet their clinical translation is constrained by the limited availability of functional cells and inefficient engraftment. Here, we review progress in the field from a translational perspective, focusing on strategies to overcome these core challenges. We analyze emerging cell sources derived from stem cell technologies and assess their therapeutic potential. These translational efforts are organized around two clinical paradigms: hepatocyte replacement for long-term functional correction and temporary hepatocyte support for liver failure. Beyond hepatocytes, we also discuss preclinical and translational advances involving other liver cell types. To conclude, we outline critical gaps that need to be addressed for clinical translation, including scalable good manufacturing practice (GMP)-compliant manufacturing, efficient preconditioning regimens, long-term immune compatibility with non-invasive graft monitoring, and patient stratification for optimal clinical outcomes. We also discuss how hepatocyte-based therapies can complement gene/RNA therapies and xenotransplantation to broaden treatment options for liver diseases.

Deborah Cipria, Tania Baccega, Miriana Rizzo et al.

Annika Wittich, Kim Krieg, Philip Gribbon et al.

Organoids are self-organizing three-dimensional (3D) in vitro tissues derived from pluripotent stem cells (PSCs) that recapitulate key structural and functional features of human organs. Their multicellular architecture and physiological relevance make them promising new approach methodologies (NAMs) for disease modeling, drug discovery, and toxicity testing. However, their reliability and scalability for compound screening remain under evaluation. This review summarizes current human PSC-derived organoid screening strategies, highlighting available readouts, related machine learning methods, and their potential advantages over traditional screening models. We also discuss major challenges, including assay robustness, throughput limitations, and the need for standardized protocols. Advancing validated and scalable approaches will be essential for integrating organoids into pharmaceutical development and improving the translational success of drug candidates.

Janssen Research & Development, LLC

The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS). Phase: PHASE3 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Myeloma Interventions: Bortezomib; Dexamethasone; Lenalidomide; Cilta-cel; Cyclophosphamide; Fludarabine

Nesrine Ebrahim, Hajir A Al Saihati, Arigue A Dessouky et al.

Severe COVID-19 is marked by a dysregulated inflammatory response, known as a cytokine storm, resulting in acute respiratory distress syndrome (ARDS) and multiple organ failure. Mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated potential as immunomodulatory agents. This work investigates the possibility of MSC-Exos to mitigate excessive inflammation in COVID-19 by targeting the mitogen-activated protein kinase (MAPK) signalling pathway.

Liping Dou

This single-center, open-label, single-arm, prospective study will evaluate the safety, tolerability, and efficacy of CD22/CD19 dual-target CAR-T cell therapy as consolidation treatment in patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) who have achieved first remission after standard induction therapy and consolidation chemotherapy. Approximately 30 patients will be enrolled. Participants will undergo screening, cell collection for CAR-T manufacturing, lymphodepleting chemotherapy, and subsequent CAR-T cell infusion, followed by scheduled safety and efficacy follow-up. Safety assessments will include monitoring for cytokine release syndrome, neurotoxicity, hematologic toxicity, organ toxicity, infections, and other adverse events. Efficacy assessments will include event-free survival, overall survival, progression-free survival, duration of response, relapse, and mortality. Exploratory analyses will assess CAR-T cell kinetic characteristics and clonal evolution after treatment. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia Interventions: CD22/CD19 Dual-Target CAR-T Cells

Lucia Y Chen, Adolfo Aleman, Marta Larrayoz et al.

T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.

Ohio State University Comprehensive Cancer Center

This phase I trial tests the safety, side effects, and best dose of anti-glycoprotein-A repetitions predominant (GARP) chimeric antigen receptor (CAR) T cell therapy and how well it works in treating patients with grade III or IV gliomas that have come back after a period of improvement (recurrent). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, such as GARP, on the patient's tumor cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain tumors. Giving anti-GARP CAR T cell therapy may be safe, tolerable, and/or effective in treating patients with recurrent grade III or IV gliomas. Phase: PHASE1 Status: RECRUITING Conditions: Recurrent Malignant Glioma; Recurrent WHO Grade 3 Glioma; Recurrent WHO Grade 4 Glioma; WHO Grade 2 Glioma; WHO Grade 3 Glioma; WHO Grade 4 Glioma Interventions: Anti-GARP Chimeric Antigen Receptor-T Cells; Biospecimen Collection; Chest Radiography; Echocardiography Test; Magnetic Resonance Imaging; Multigated Acquisition Scan; Pheresis; Surgical Procedure

Jeffrey Veale, MD

The purpose of this study is to find out if an investigational treatment will allow kidney transplant recipients to better accept their new kidney and stop immunosuppressive medicines. This study is for kidney transplant recipients who receive a kidney from a sibling donor. The investigational treatment is started after kidney transplant. It begins with a regimen of a drug called rabbit anti-thymocyte globulin (rATG) combined with radiation therapy (known as total lymphoid irradiation, or TLI) to the lymph nodes and spleen. This is followed by an infusion of blood stem cells, which will be donated by the same sibling who donated their kidney. Researchers think that this treatment allows immune cells from the donor and recipient to live side by side, a condition referred to as "mixed chimerism." Mixed chimerism may help create a state of "tolerance" in kidney transplant recipients in which all immunosuppressive medications can be stopped without rejection of the transplanted kidney. This study will test whether (1) the investigational treatment will allow patients to stop immunosuppressive medications after their kidney transplant and (2) if the treatment impacts the rate of kidney rejection and the side effects of immunosuppressive medications. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Renal Transplant Rejection; Tolerance; Kidney Transplant Interventions: Donor CD34+ and CD3+ cells

National Cancer Institute (NCI)

Background: Allogeneic hematopoietic stem cell transplant involves taking blood stem cells from a donor and giving them to a recipient. The transplants are used to treat certain diseases and cancers. Researchers want to see if the transplant can treat VEXAS Syndrome. Objective: To see if stem cell transplants can be successfully performed in people with VEXAS and even improve the disease. Eligibility: People ages 18-75 who have VEXAS Syndrome that has caused significant health problems and standard treatment either has not worked or is not available. Design: Participants will be screened with: Physical exam Medical review Blood and urine tests Heart and lung function tests Bone marrow biopsy Participants will have a chest x-ray. They will have an imaging scan of the head, chest, abdomen, pelvis, and sinus. They will have a bone density scan. They will have a dental exam and eye exam. They will meet with specialists. They will repeat some screening tests. Participants will be admitted to the NIH hospital. They have a central venous catheter put into a vein in the chest or neck. They will receive drugs to prepare their bone marrow for the transplant. They may have total body irradiation. They will receive the donor stem cells through the catheter. They will get other drugs to prevent complications and infections. After discharge, they must stay in the DC area for 3 months for weekly study visits. Participants will have study visits 30, 60, 100, 180, 210, 240, 300, and 360 days later. After that, they will have yearly visits for 2 years and then be contacted yearly by phone.... Phase: PHASE2 Status: RECRUITING Conditions: Immunodeficiency; Hematopoietic Stem Cell Transplantation Interventions: Allogeneic HSCT; Busulfan test dose; Mycophenolate mofetil (MMF); Tacrolimus; Busulfan; Total Body Irradiation (TBI); Fludarabine; Cyclophosphamide (CY); Post-Transplant Cyclophosphamide (PTCY)

New York Medical College

Patients with relapsed low-risk CD30 classical Hodgkin Lymphoma will have autologous CD30 CAR T-cell manufactured. Dose escalation will be used to determine the RP2D. Following lymphodepletion, CAR T-cell will be infused. Phase: PHASE1 Status: NOT_YET_RECRUITING Conditions: Classical Hodgkin Lymphoma Interventions: CD30+ CAR T-cells; Bendamustin; Fludarabine

Mark R. Dowling, Edward R. Scheffer Cliff, Anthony Jeffrey et al.

Abstract In this retrospective analysis of 584 patients who received chimeric antigen receptor T-cell therapy for large B-cell lymphoma at 6 Australian centers, no association was found between time of infusion and outcome, accounting for confounders, suggesting minimal clinical impact of chronobiology in this setting.

National Cancer Institute (NCI)

Background: CAR T-cell therapy is a promising new treatment for blood cancers. During treatment, a person s T-cells are genetically changed to kill cancer cells. Researchers want to learn more about the effects of potential problems that may be associated with this treatment. We are specifically interested in learning if and how this treatment may affect the brain or your thinking skills. Objective: To learn if CAR T-cell therapy can affect how children and adults think, process, and remember things. Eligibility: People aged 5-35 who have blood cancer that has not responded to treatment, or the blood cancer has come back after treatment, and who will receive CAR T-cell therapy. Caregivers are also needed. All participants must be able to speak and read in English or Spanish. Design: Participants will be screened with a medical history. Information from participants medical records will be collected. Participants will take tests at home or at NIH to see how well they think, read, learn, remember, reason, and pay attention. The tests will be both computerized and paper/pencil. They will take less than 1 hour to complete. Participants and a parent/adult observer will complete a 5-minute Background Information Form and a checklist of nervous system symptoms. If participants are 5 years or older, they will participate in activities to test their ability to do different thinking tasks, like answer questions, complete puzzle patterns, and remember things. Participants and their caregivers will complete questions to see if they are having specific symptoms related to receiving CAR T-cells. The questions will assess their well-being and needs. The questions will take less than 1 hour to complete. Some tests and questions will be repeated at different time points in the study. Participation will last for up to 3 years.... Status: RECRUITING Conditions: Lymphoma; Leukemia

Abhishek K Singh, Kathrine S Rallis, Jose A Cancelas

Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca&#xb2;&#x207a; overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies.

Niels W. C. J. van de Donk, Pieter Sonneveld, Hermann Einsele

Abstract B-cell maturation antigen (BCMA)– or G protein–coupled receptor class C group 5 member D (GPRC5D)–directed T-cell immunotherapies have substantially improved the survival of patients with relapsed/refractory multiple myeloma (MM). Despite these advances, a subset of patients does not respond, and most patients will eventually relapse. Tumor heterogeneity, resulting in rapid selection of both antigen-negative and antigen-low cells, is a critical issue affecting response to T-cell immunotherapies targeting single tumor-associated antigens. In addition, antigen escape (due to deletions, mutations, or epigenetic alterations) is frequently observed in patients who experience disease progression after chimeric antigen receptor (CAR) T-cell infusion or during bispecific antibody (BsAb) treatment. Simultaneous targeting of 2 tumor-associated antigens may improve efficacy by addressing heterogeneous target expression and preventing antigen escape. Various dual-targeting strategies are currently evaluated in MM, including the combination of 2 single-antigen–targeting BsAbs. Of note, the efficacy of the combination of teclistamab and talquetamab appears to have enhanced anti-MM activity, compared with the corresponding conventional BsAbs alone in similar patient populations. Furthermore, dual-antigen targeting with T-cell–redirecting trispecific antibodies (eg, ramantamig [BCMA×GPRC5D] and ISB 2001 [BCMA×CD38]) has already demonstrated promising results in heavily pretreated MM. Studies with limited numbers of patients have demonstrated that CAR T-cell products with specificity for >1 antigen are also effective in advanced MM; however, at this time, none of the dual-targeting CAR T-cell products has been shown to be clearly superior to targeting BCMA alone with ciltacabtagene autoleucel. Dual targeting should eventually be compared in large phase 3 trials with the classical approach of serial treatment with monotargeting agents with target switch.

Northwestern University

This phase II trial tests how well pembrolizumab and tazemetostat work to treat patients who have received autologous stem cell transplantation (ASCT) or chimeric antigen receptor (CAR) T cell therapy for aggressive non hodgkins lymphoma. A monoclonal antibody, such as pembrolizumab, is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and tazemetostat may work better to treat patients who have received ASCT or CAR-T cell therapy for aggressive non hodgkins lymphoma. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: B-Cell Non-Hodgkin Lymphoma Interventions: Biospecimen Collection; Computed Tomography; Echocardiography; Pembrolizumab; Positron Emission Tomography; Tazemetostat

Mark P. Hamilton, Partow Kebriaei

Poseida Therapeutics, Inc.

Phase 1 study comprised of open-label, dose escalation and expansion cohort study of P-CD19CD20-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed/refractory B cell malignancies Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; High-grade B-cell Lymphoma; Primary Mediastinal Large B-cell Lymphoma (PMBCL); Transformed Follicular Lymphoma (tFL); Follicular Lymphoma Grade 3B; DLBCL; DLBCL - Diffuse Large B Cell Lymphoma; DLBCL Arising From Follicular Lymphoma; DLBCL, Diffused Large B Cell Lymphoma; DLBCL NOS Interventions: P-CD19CD20-ALLO1; Rimiducid

Wondercel Biotech (ShenZhen)

This is an investigator initiated trial to assess the efficacy and safety of a GPC3-targeting CAR-T therapy (REVO-UWD-03) in the HCC and Lung Cancer. It also aims to explore the feasibility of using a novel universal CAR-T cell platform. Phase: EARLY_PHASE1 Status: SUSPENDED Conditions: HCC - Hepatocellular Carcinoma; NSCLC (Advanced Non-small Cell Lung Cancer) Interventions: Universal CAR-T cells injection for treating HCC and NSCLC; MMF Immunosuppression

Mathew Nickel Maunu, Ingrid Meulenbelt, Yolande F M Ramos

Stem cells are key for development of disease modeling and therapies. While promising, however, current application of cutting-edge hiPSC technologies is, among others, confounded by cellular heterogeneity leading to concerns about their suitability for experimental and clinical applications. Variations across donors, tissue sources, methodologies, and analytical challenges, together contribute to the observed heterogeneity. Hence, increased understanding of heterogeneity in stem cell research is essential to advance development of reliable tissue models and effective therapies. In this review, we summarize current knowledge regarding the origins of cellular heterogeneity in hiPSC-derivatives. Differentiation protocols can be improved through the application of novel media morphogens, integration with new biomaterials and physical strategies (e.g. 3D culture, mechanical stimulation). Additionally, standardization of methods and regulations for generation and application of cell lines and neo-tissues, thorough characterization, central banking, and registration of cells will reduce variation and increase experimental reproducibility. As reliable reference datasets become more abundant the continuous development of analytical tools as well as advanced application of artificial intelligence to analyze -omics datasets will become more refined. This will aid identification of different cell types in heterogeneous cell populations and key factors driving off-target differentiation. We provide recommendations for best practices throughout the stem cell research pipeline and discuss opportunities to advance broad applicability of stem cells for disease modeling and beyond through concerted efforts to improve experimental robustness and analytical accuracy. Finally, we advocate that certain heterogeneity may be essential in development of laboratory models to faithfully mimic the in vivo situation.

Wondercel Biotech (ShenZhen)

This study is a single-arm, single-center, investigator-initiated clinical trial. The primary objective is to evaluate the safety and preliminary efficacy of administering universal CD19 CAR-T cells to subjects with refractory and relapsed B-cell tumors. Eligible participants will undergo FC lymphodepleting chemotherapy preconditioning after signing an informed consent form, followed by a one-time injection of universal UWD-19 to assess its safety and efficacy. Subjects will be hospitalized for a period, and after discharge, they will undergo periodic efficacy assessments and long-term survival follow-up for at least five years. Phase: EARLY_PHASE1 Status: SUSPENDED Conditions: B Cell Lymphoma; B Cell Leukemia; B Cell Malignancy Interventions: Single dose injection of certain dose of UWD-19; MMF Immunosuppression

Royan Institute

Dopason is a phase I, open-label, multicenter, single-arm clinical trial designed to evaluate the safety and feasibility of intraputaminal transplantation of human embryonic stem cell-derived dopaminergic progenitor cells (DopaCells) in patients with moderately severe Parkinson's disease. Phase: PHASE1 Status: RECRUITING Conditions: Parkinson Disease (PD) Interventions: Dopacell; Immunosuppressive Regimen; Customized microinjection device

National Institutes of Health Clinical Center (CC)

This study will evaluate the long-term functional status, psychosocial adjustment and quality of life of patients with different types of diseases and conditions who have had an allogeneic (donor) stem cell transplant. Information from this study may help patients and families know better what they may expect long-term after transplant and will help health care workers improve services to aid in patients' recovery. People 18 years of age or older who have had an allogeneic stem cell transplant three or more years before the start of this study may be eligible to participate. Participants complete a series of questionnaires once a year for three years. The questionnaires take about 40 minutes to complete and include information on patient demographics, patients' physical, social, and emotional functioning, spiritual well being, pain, mental health, general health, fatigue, and other areas of health-related quality of life. The questionnaires are completed at home or during normally scheduled follow-up visits to the NIH. ... Status: COMPLETED Conditions: Long Term Psychological Affects on HSCT

The First Affiliated Hospital of Soochow University

This is a single-arm, open-label, single-center, phase I/II study to determine the safety and efficacy of CD19 CAR-T(ssCART-19) combined with autologous T cells engineered to express CD19, namely CD19+ feeding T cells (FTCs), as consolidation therapy in patients diagnosed with de novo Philadelphia chromosome-positive CD19+ B-ALL. The study will contain the following sequential phases: screening, lymphocyte apheresis, induction, and consolidation chemotherapies combined with tyrosine kinase inhibitors. Once in complete response, patients will receive two to four cycles of ssCART-19s, namely one cycle of ssCART-19 infusion (CAR-T1) followed by one to three cycles of ssCART-19 and CD19+ FTC infusion (CAR-T2-4). The role of CD19+ FTCs is to mimic leukemia cells. Therefore, they are expected to stimulate in vivo expansion and persistence of ssCART-19. Considering the limited number of lymphocytes obtained by a single apheresis from patients and cost-efficacy, in addition to safety, we will explore the range of biologically active doses of FTCs in a phase I study. Based on preclinical data, FTCs' stimulation of ssCART-19 at a ratio of 1:1 could achieve the best activation response, so a 5×10\^6/kg dosage of FTCs was set as the initial dosage in the study, and lower doses were also evaluated. In phase I, FTCs will be administered at the dose of 5×10\^6/kg, 3.25×10\^6/kg, or 2×10\^6/kg two hours after ssCART-19 infusion on day 1 and once again administered at the same dose on day 8. After ssCART-19 and FTCs infusion, adverse events (AEs) as the primary endpoints will be recorded for 6 months; efficacy as the secondary endpoint will be assessed by detecting molecular response for 6 months, PFS, and OS for 2 years. In phase II, we will expand the study at optimal biological doses of FTCs and further evaluate the efficacy and safety of the innovative combination therapy of ssCART-19 and FTCs. The primary endpoint was the complete molecular response (CMR). The secondary endpoints were RFS, OS, and adverse events (AEs) of the patients. Phase: PHASE1, PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Acute Lymphoblastic Leukemia, Adult B-Cell Interventions: ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion; ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion; ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion; ssCART-19 cells combined with CD19+ feeding T cells (FTCs) infusion

National Institutes of Health Clinical Center (CC)

Background: \- People who have an allogeneic hematopoietic stem cell transplant (HSCT) need help as they recover. Being a caregiver can be stressful to the body and mind. Researchers want to find ways to reduce this stress. Objective: \- To see how a stress reduction intervention affects the stress levels and health of an HSCT caregiver. Eligibility: \- Adults age 18 and older who plan to be an active caregiver for a person having their first allogeneic HSCT at the NIH Clinical Center. An active caregiver is someone who will be caring for the person from just before admission for the HSCT until at least 6 weeks after. Design: * Participants will be put in either the intervention group or the control group. * All participants will get the usual caregiver education given to all patients and caregivers having a stem cell transplant at the NIH Clinical Center. * All participants will have 2 study visits. They will give blood samples. They will have health assessments and brief physical exams. They will fill out study questionnaires and have an exit interview. * The intervention group will get an MP3 player. It will have an audio file with a stress reduction intervention on it. Participants will do this intervention daily. It takes 20 minutes. They will do gentle stretches and breathing exercises. They will get a diary to track their practice. * The intervention group also will have follow-up phone calls 2 and 4 weeks after their first clinic visit. * The person getting the HSCT will not be actively involved in the study. * The study will last about 2 months. Phase: PHASE2 Status: COMPLETED Conditions: Stress, Psychological; Caregivers Interventions: Stress reduction intervention

National Cancer Institute (NCI)

Background: \- Gene therapy is being investigated as a possible treatment for individuals with immunodeficiency diseases or other conditions that make it difficult to fight off infection. Gene therapy avoids problems with donor identification and possible rejection of bone marrow transplant by using the patient s own modified blood cells to help treat the disease. Researchers are interested in collecting stem cells from the blood of individuals with immunodeficiency diseases in order to use the cells to develop potential gene therapy treatments. Objectives: \- To collect blood stem cells from patients with immunodeficiency diseases tto test our ability to correct the defects of these cells in the test tube. Eligibility: * Individuals between 18 and 40 years of age with immunodeficiency diseases. * Individuals with human immunodeficiency virus (HIV) will not be able to participate in this study. Design: * Participants will provide an initial blood sample for disease screening (such as hepatitis B and C, syphilis, or viruses like the Epstein-Barr virus, herpes simplex virus, or toxoplasmosis) and to check kidney and liver function. * Starting 5 days before blood donation, participants will receive daily injections of a drug called G-CSF (granulocyte colony stimulating factor, or filgrastim), which pushes stem cells out of the bone marrow and into the bloodstream. Participants will receive the injections at the National Institutes of Health Clinical Center. * On day 5, participants will have a single leukapheresis procedure to collect the stem cells from the blood. * No additional treatment will be provided as part of this protocol. The cells that are collected will be used fore experiments in the lab and will not be used to treat individuals with these diseases. Status: RECRUITING Conditions: LAD-1; DOCK8; GATA2 Deficancy

Mohammad Amin Bakhshan, Leila Chodari, Sayyed Jafar Hasani et al.

Brain tumors rank among the most lethal cancer types, accounting for high mortality rates in both pediatric and adult populations. They present formidable therapeutic obstacles owing to their intrinsically aggressive biology, the complexity of their surrounding microenvironment, and the relatively poor efficacy of existing standard treatment modalities. Mesenchymal stem cells (MSCs) have garnered significant interest in oncology research due to their inherent ability to migrate selectively toward tumor sites and their versatility as delivery vehicles for a wide range of therapeutic agents. This review highlights the diverse therapeutic roles of MSCs and their derivatives, such as exosomes and engineered vectors, in brain tumor management. It encompasses key therapeutic strategies leveraging MSCs, including MSC-mediated delivery of chemotherapeutic agents, oncolytic viruses, and therapeutic genes; exosome-based interventions; nanotechnology-enhanced targeting precision; and the modulation of tumor behavior by engineered MSC-derived cytokines. Despite their promise, concerns remain regarding the potential for MSCs to promote tumor growth and the need for precise delivery systems. This review highlights the crucial need for additional research to refine MSC-based strategies, particularly through the rational engineering of MSCs and their derivatives for multimodal therapeutic applications, with the goal of enhancing specificity, efficacy, and safety in the treatment of malignant brain tumors.

Martina Pigazzi, Silvia Merlini, Ambra Da Ros et al.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.

UPECLIN HC FM Botucatu Unesp

Peripheral arterial disease (PAD) can progress to critical limb ischemia (CLI) of the affected lower limb, characterized by pain at rest, ulcerations or gangrene, with a high risk of amputation. In this phase, the best treatment is arterial limb revascularization, but this is not always possible or even effective for promoting pain relief, healing of ulcers or preventing amputations, in addition to the high socioeconomic cost caused by the disease. Recent advances in cell therapy represent a promising supporting alternative for the treatment of PAD in cases where conventional alternatives have run out. Objective: To evaluate the safety and efficacy of cell therapy with expanded autologous mesenchymal stem cells in the treatment of patients with PAD with CLI and chronic arterial ulcers. Methods: An open randomized clinical study will be performed with 2 groups of 20 patients with CLI: in group 1, a fragment of abdominal fat tissue (10g) will be collected to obtain mesenchymal stem cells, which will be expanded and applied using subcutaneous perilesional injection in the affected lower limb, in addition to the application in the form of a personalized curative biological on the wounds. Group 2 will receive conventional treatment with a Hydrogel dressing with essential fatty acids. Periodic clinical evaluations, complementary exams and photographic record will be carried out. The main outcome of effectiveness will be partial or total wound healing. Safety outcomes will be monitored for infections, gangrene, amputations and deaths. Participants will be monitored for 120 days. Major amputation cases will not be included. An independent external evaluator and blind to the groups will evaluate the results. It is an innovative procedure with high impact and financial return for SUS, in view of the high prevalence of the disease and the high socioeconomic impact of the disease when it progresses to limb amputation. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Peripheral Arterial Disease; Leg Ulcer Interventions: CELULAS TRONCO; CONVENTIONAL DRESSING

Nina B Horowitz, Imran A Mohammad, June Ho Shin et al.

Human tissue-resident natural killer (NK) cells (trNK cells), broadly defined by markers of tissue residency, such as CD49a [integrin &#x3b1;1 (itga1)] and CD103 [integrin &#x3b1;e (itgae)], are increasingly recognized for their immunoregulatory role in host control of infection, malignancy, and autoimmunity. Although the importance of transforming growth factor-&#x3b2; in trNK cell differentiation has been demonstrated, the context in which the differentiation of CD49a+CD103+ trNK cells occurs can result in either an immunosuppressive phenotype (e.g., decidual NK cells) or a highly cytotoxic one (e.g., some tumor trNK subsets). To understand this dichotomy better, we used a multiomic approach to molecularly characterize these cells. We identified a cytotoxic trNK (ctrNK) cell population, characterized by the expression of CD39. These ctrNK cells exhibited superior cytolytic activity against tumor target cells, enhanced capacity to infiltrate into solid tumor microenvironments, and augmented ability to control solid tumor growth in vivo compared with conventionally activated peripheral NK cells. This heightened cytolytic and infiltrative functionality of ctrNK cells appeared to be conferred, in part, by the expression of CD103 and by avidity for tumor targets. Because adoptive immune cell therapy of solid tumor malignancies has been challenged by the inefficiency of ex vivo expanded immune cells to infiltrate immunosuppressive solid tumor microenvironments, our observations that ctrNK cells can be differentiated and expanded ex vivo present a potential platform for adoptive cell therapy of solid tumor malignancies.

Amy McCaughey-Chapman, Bronwen Connor

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterised by the loss of GABAergic medium spiny neurons (MSNs). Cellular models of HD are mainly derived from human embryonic stem cells or induced pluripotent stem cells. These models are limited by their DNA embryonic age, low neuronal yields and limited disease pathology. We propose direct reprogramming, which maintains the aging signature of the cells, to human induced lateral ganglionic eminence precursors (hiLGEP) results in the generation of high yields of functionally mature MSNs exhibiting pathological hallmarks of HD. hiLGEPs were derived from normal and HD fibroblasts by direct reprogramming and differentiated to MSNs. hiLGEP and MSN fate acquisition was compared between normal and HD through gene and protein expression. Known pathological hallmarks of HD were investigated within the hiLGEP-derived MSNs. The formation of functional synapses was investigated using live cell calcium imaging. We demonstrate that HD fibroblasts can be reprogrammed to hiLGEPs expressing key linage markers and displaying disease-related changes in expression of FOXP1 and FOXP2. HD hiLGEPs can be differentiated to high yields of MSNs co-expressing DARPP32, GABA, or GAD65/67, and SYN1 and PSD-95. HD MSNs show a reduced expression of BDNF, HAP1, TRKB, Rhes and PGC1&#x3b1;, exhibit MW8+ mHTT aggregates and display smaller cell somas, reduced total neurite length and reduced branched neurites when compared to normal MSNs. An administration of 100&#x2009;&#xb5;M dopamine was necessary to generate a calcium response in HD MSNs. This study establishes a directly reprogrammed hiLGEP-derived MSN model of HD which recapitulates pathological signatures.

Sara Tomei, Tom S Weber, Shalin H Naik

Haematopoiesis is a tightly regulated process through which a small pool of stem cells sustains the lifelong production of all blood cell types in response to physiological demand. Understanding how this process is controlled, and how haematopoietic stem cells (HSCs) commit to specific lineages, is essential to fine tune immune cell production both in vivo and in vitro for cell therapy applications. In this review, we examine the major conceptual frameworks that have been proposed to describe haematopoiesis and the underlying data that informed them, ranging from the classical discrete hierarchy to the continuous model, the punctuated continuum, and the multi-track model. Evidence from clonal lineage-tracing studies in mouse, non-human primates, and humans supports the idea that lineage fate is largely predetermined rather than stochastically acquired, and we highlight the importance of clonal multi-omics approaches for identifying the molecular predictors of fate. We then discuss the computational models that have been developed to study haematopoietic development. Finally, we outline key challenges, including resolving native haematopoiesis in vivo, in both mouse and humans, and identifying the molecular programs that encode fate trajectories and how they are altered in disease. Looking at the haematopoietic process through a clonal lens is paramount to find the molecular signatures that truly can predict fate.

Paul Scholz, Jared Thompson, Kadin T. Crosby et al.

Xi Lin, Chloe Hyun-Jung Lee, Ting Zhang et al.

Mayo Clinic

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression. The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with MSA. Funding source: FDA Office of Orphan Product Development (OOPD), Mayo Clinic Executive Dean for Research Transformational Award, Mayo Clinic Regenerative Medicine, and Mayo Clinic Department of Neurology. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple System Atrophy Interventions: Autologous Mesenchymal Stem Cells; Placebo

University of Washington

This phase II trial tests the effectiveness of odronextamab given before chimeric antigen receptor T (CAR-T) cell therapy (bridging therapy) in patients with large B-cell lymphomas that have come back after a period of improvement (relapsed) or that have not responded to previous treatment (refractory). Odronextamab is a bispecific antibody that can bind to two different antigens at the same time. Odronextamab binds to CD3, a T-cell surface antigen, and CD20 (a tumor-associated antigen that is expressed on B-cells during most stages of B-cell development and is often overexpressed in B-cell cancers) and may interfere with the ability of cancer cells to grow and spread. Bridging therapy has been used to maintain disease control and to increase the chance of successful receipt of CAR-T cell therapy. However, bridging therapy is typically given after leukapheresis, which does not help prevent disease progression between the decision for CAR-T cell therapy and leukapheresis. Giving odronextamab as bridging therapy before leukapheresis may delay disease progression to allow leukapheresis and increase the likelihood of successful CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphomas. Phase: PHASE2 Status: RECRUITING Conditions: Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Grade 3b Follicular Lymphoma; Recurrent High Grade B-Cell Lymphoma; Recurrent Primary Mediastinal Large B-Cell Lymphoma; Recurrent Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Refractory Grade 3b Follicular Lymphoma; Refractory High Grade B-Cell Lymphoma; Refractory Primary Mediastinal Large B-Cell Lymphoma; Refractory Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma Interventions: Odronextamab; Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Chimeric Antigen Receptor T-Cell Therapy; Computed Tomography; Leukapheresis; Lumbar Puncture; Positron Emission Tomography; Questionnaire Administration; Biopsy Procedure

David R. Ziehr, Fei Li, K. Mark Parnell et al.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. Although glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how monocarboxylate transporters (MCTs) 1 and 4, key pulmonary lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings revealed that inhibiting MCT1 or MCT4 using RNA interference or small molecules reduced transforming growth factor–β1 (TGFβ)–stimulated myofibroblast differentiation in lung fibroblasts from healthy donors and patients with idiopathic pulmonary fibrosis. Small-molecule MCT inhibitors also decreased bleomycin-induced pulmonary fibrosis in C57Bl6/N mice aged 10 to 12 weeks. Through bioenergetic analyses, stable isotope tracing, metabolomics, and imaging mass spectrometry in both human cells and mice, we demonstrate that inhibiting lactate transport enhanced oxidative phosphorylation, reduced reactive oxygen species production, and diminished glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, an MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors as a therapy for patients with limited treatment options.

University of Taipei

In this 3-year project, investigators will first measure stem cells (primary outcome) and immune cells (secondary outcome) in human skeletal muscle immediately after and 24 hour after the BFR-training. In the second and third year, the effect of β-NMN (vitamin B3 precursor) and antioxidant on the same outcomes after BFR-exercise will be assessed. The BFR-exercise in the study will consist of a 5 × 10-second sprinting with maximal voluntary efforts, 5 minutes after a BFR pre-conditioning to legs using pressurized cuffs. In Study 1 (1st year, N = 24, aged 20-30 year), a randomized crossover trial will be conducted to compare the efficacy of sprinting exercise using BFR pre-conditioning at 20 mmHg (control) or 180 mmHg (occlusion). Study 2 (2nd year, N = 24, aged 20-30 years) will be conducted to examine the effect of β-NMN supplementation on the aforementioned outcomes in human muscles using a randomized placebo-controlled crossover study design. Study 3 (third year, N = 24, aged 20-30 years) will be conducted to examine the effect of vitamin C on the same variables immediately after and 24 hours after resistance exercise intervention, using a randomized placebo-controlled crossover study design. Phase: NA Status: COMPLETED Conditions: Exercise; Blood Flow Restriction (BFR) Training Effects; Supplement Interventions: BFR (180 mmHg); NMN-BFR exercise; Vitamin C-resistance exercise

Haruko Nakano, Naofumi Kawahira, Alexander Vesprey et al.

Glucose serves not only as an energy source but also as a signaling molecule for organ growth. Intrauterine hyperglycemia elevates the risk of congenital heart defects independently of genetic factors, although its underlying mechanisms remain unclear. In this study, we investigated the impact of maternal hyperglycemia on cardiac development using a diabetic pregnancy mouse model and pluripotent stem cell-derived cardiomyocytes. Multi-modal analysis revealed that hyperglycemia disrupts mitochondrial structure and function in fetal hearts even before overt malformations appear, indicating that mitochondrial immaturity is an early signature of diabetic embryopathy. Metabolomic profiling revealed nucleotide imbalance and subsequent AMP-activated protein kinase (AMPK) suppression-contrasting with reports of increased AMPK activity observed in hyperglycemic neural tube defects. Notably, pharmacological activation of AMPK restored cardiomyocyte and mitochondrial function under high-glucose conditions in vitro. Our findings demonstrate that high glucose inhibits cardiomyocyte maturation through dysregulated nucleotide metabolism and AMPK suppression, advancing understanding of hyperglycemia-induced cardiac developmental defects.

David Wald

This study seeks to determine the safety and efficacy of the infusion of autologous CD19 CAR-T cells that are manufactured using an ultra-fast process. Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Non Hodgkin Lymphoma Interventions: UF-KURE19 CAR-T cells; Fludarabine; Cyclophosphamide

M.D. Anderson Cancer Center

To look at the safety and effectiveness of emapalumab for the treatment of prolonged severe cytopenia in participants with LBCL who receive CART. Phase: PHASE2 Status: RECRUITING Conditions: Cytopenia Interventions: Emapalumab

Yuan Liu, Jingwen Yang, Madiha Iqbal et al.

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced treatment outcomes for hematological malignancies; however, therapy-associated toxicities are often severe and sex-related differences in toxicity remain under-investigated. Here, we extract data from FDA Adverse Event Reporting System (FAERS) to evaluate sex-associated differences in CAR T-cell therapy toxicities. Among 7700 cases, females show higher reporting odds of cytokine release syndrome (CRS), with a reporting odds ratio (ROR) of 1.10 and a confidence interval (CI) of [1.00, 1.20], as well as leukemias (ROR&#x2009;=&#x2009;1.34; CI [1.05, 1.70]). Elevated reporting odds in females are observed across multiple organ systems. Comparisons across cancer treatments indicate that sex-associated reporting patterns in CAR T-cell therapy cannot be attributed to baseline sex differences across cancer therapies. Stratified analyses further identify heterogeneity by cancer type and CAR T product. These results highlight distinct sex-associated toxicity patterns and may support incorporating sex into toxicity management.

Christopher A Procyk, Anna Melati, Menahil Tariq et al.

Targeted photoreceptor replacement therapy is a promising, potentially disease-agnostic approach for reversing sight-loss associated with advanced retinal degenerations, including age-related macular degeneration. We have previously shown that transplantation of human stem cell-derived cone photoreceptors (hCones) into young adult (3-month-old) mouse models of advanced retinal degeneration can restore retinal function. However, substantial remodeling of the remaining inner retinal circuitry continues long after complete photoreceptor loss, raising the critical question of whether photoreceptor transplantation can effectively rescue function at very late-stage degeneration. rd1 mice received transplants at 12-15&#x2009;months of age and were examined &#x223c;3&#x2009;months later. Transplanted hCones survived in large numbers, while host inner retinal neurons exhibited significant plasticity, extending dendrites to transplanted hCones, and making synapse-like contacts. Host M&#xfc;ller glia undergo notable remodeling, apparently incorporating the donor cells within the retinal structure. Multielectrode array recordings showed robust rescue of light-evoked activity across the normal photopic range intensities and evidence of inner retinal processing, while some treated mice showed improvements in visually-evoked optokinetic head tracking behavior. Together, these data indicate that effective rescue following photoreceptor replacement therapy is feasible long after complete photoreceptor loss and extensive inner retinal remodeling.

Xinyan Chen, Chenzhi Lai, Tian He et al.

Craniosynostosis is a congenital disorder characterized by premature suture fusion and aberrant skull morphogenesis. The cellular dynamics and regulatory mechanisms of suture mesenchymal stem cells (SuSCs) in this disease remain poorly defined.

Weiqian Li, Yue Huo, Zhaoru Zhang et al.

Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3' untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, Nat10 deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3' untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation-an effect independent of NAT10's ac4C catalytic activity. Moreover, NAT10 dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.

Cristina Cosentino, Rémy Klein, Véronique Menoud et al.

Abstract Obesity and diabetes impose chronic stress on pancreatic β-cells, while reprogramming of islet-resident macrophages (iMACs) accelerates dysfunction. Here, we identify transfer RNA-derived fragments (tRFs) as previously unrecognized mediators of islet remodeling under metabolic stress. 5’tRF Glu(CTC) and 5’tRF Gly(GCC) are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5’tRF Glu(CTC) also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5’tRF biogenesis, and targeted inhibition of 5’tRF Glu(CTC) preserves β-cell viability and function under palmitate exposure. In a β-cell/macrophage co-culture model, β-cell contact shapes a distinct iMAC-like phenotype that shifts after palmitate treatment. Inhibiting 5’tRF Glu(CTC) in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5’tRF Glu(CTC) interacts with RNA-binding proteins to control immune activation, extracellular matrix remodeling, and oxidative stress pathways. These findings position tRFs as central effectors of cellular stress responses in both endocrine and immune cells.

University of Colorado, Denver

This trial will determine whether adding ruxolitinib to a reduced intensity conditioning (RIC) regimen reduces the rate of graft failure following haploidentical (haplo) hematopoietic cell transplant (HCT) for children and young adults with sickle cell disease (SCD). This study will enroll and treat up to 24 participants. Recruitment is expected to last for about 2 years and participants will be followed for an additional 2 years post-HCT. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Sickle Cell Disease; Hematopoetic Stem Cell Transplant; Haploidentical Hematopoietic Stem Cell Transplant; Haploidentical Stem Cell Transplantation; Graft Failure Interventions: Ruxolitinib

Acorn Biolabs Inc.

Secretome treatment for facial rejuvenation Phase: EARLY_PHASE1 Status: RECRUITING Conditions: Facial Aging; Rejuvenation; Stem Cell; Stem Cell Banking Interventions: Autologous Hair Follicle-Derived Secretome; Control Saline

Novartis Pharmaceuticals

This is a Phase I/II, open-label, non-randomized, multi-center study in patients with extensive-stage small cell lung cancer (ES-SCLC) to determine the recommended dose(s) (RD) and to evaluate the safety, tolerability and preliminary efficacy of DJI136. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Extensive-stage Small Cell Lung Cancer (ES-SCLC) Interventions: DJI136

National Cancer Institute (NCI)

Background: Chronic lymphocytic leukemia (CLL),small lymphocytic lymphoma (SLL) and B-cell acute lymphoblastic leukemia or lymphoma (ALL) are blood cancers that affect certain white blood cells. Advanced forms of these diseases are difficult to treat. CD19 is a protein often found on the surfaces of these cancer cells. Researchers can modify a person's own immune cells (T cells) to target CD19. When these modified T cells are returned to the body-a treatment called anti-CD19 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells. Objective: To test anti-CD19 CAR T cell therapy in people with CLL or SLL and ALL. Eligibility: People aged 18 years and older with CLL or SLL and ALL that has not been controlled with standard drugs. Design: Participants will be screened. They will have imaging scans and tests of their heart function. If a sample of tissue from their tumor is not available, a new one may be taken; the sample will be tested for CD19. Participants will receive a drug to reduce the leukemia cells in their blood. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be gene edited to make them attack cells with CD19. Participants will take drugs to prepare them for treatment for 3 days. These drugs will start 5 days before the treatment. Then their own modified CAR T cells will be returned to their bloodstream. Participants will stay in the hospital for at least 9 days after the treatment. Follow-up visits will continue for 5 years. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Leukemia, Lymphocytic, Chronic, B-Cell; B-Lymphocytic Leukemia, Chronic; B-Cell Chronic Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; Lymphoblastic Lymphoma; Leukemia, Acute Lymphoblastic; Small Lymphocytic Lymphoma Interventions: Autologous HuCD19 ( Anti-CD19)CAR T cells; Cyclophosphamide; Fludarabine; Rituximab

The First Affiliated Hospital of Xinxiang Medical College

The commercial decalcified bone scaffold combined with the patient's autologous bone marrow mesenchymal stem cells was used for in vitro culture to form tissue-engineered bone, and the effect of this tissue-engineered bone in early non-traumatic femoral head necrosis was explored. Phase: NA Status: RECRUITING Conditions: Avascular Necrosis of Femur Head Interventions: Tissue-engineered bone

Jonas Jawad, Mohammad Z Khan, Tamer Jabsheh et al.

Heart failure remains a leading global cause of morbidity and mortality, with limited capacity for myocardial regeneration following infarction. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a promising therapeutic resource due to their scalability, differentiation potential, and immunologic adaptability. Engineered cardiac patches, three-dimensional constructs of hiPSC-CMs combined with supporting cells and scaffolds, offer a strategy to deliver organized myocardium directly to injured hearts, overcoming the limitations of cell injection therapies.

Asl&#x131; Ak, Dorian Luijkx, Daniel Carvalho et al.

Successful embryo implantation requires timely acquisition of endometrial receptivity, yet the epithelial mechanisms governing this transition remain poorly understood and difficult to study in humans. Current clinical assessments rely largely on transcriptomic markers, despite limited evidence that these predict functional implantation outcomes. Here, we present a human endometrium-on-chip model that enables controlled hormonal priming and quantitative measurement of blastoid attachment to patient-derived luminal epithelium. We show that hormonally primed epithelial monolayers maintain attachment competence across extended progesterone exposure, indicating a sustained permissive state rather than a sharply defined window of implantation. Single-cell RNA sequencing reveals a continuous maturation trajectory that is decoupled from functional adhesion. The model further recapitulates localized epithelial remodeling at blastoid contact sites. Together, this system provides a mechanistic framework to interrogate epithelial determinants of implantation, challenges marker-based definitions of receptivity, and offers a foundation for future diagnostic and personalized applications in medically assisted reproduction.

Xiaomin Su, Fang Yang, Jitesh Neupane et al.

Luca Gattinoni, Gabriele Inchingolo, Dennis C Harrer et al.

Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (Tscm) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR Tscm cells induced mild cytokine-release syndrome, dominated by IFN-&#x3b3;. Both products differentiated into effectors; however, only CAR Tscm cells robustly reconstituted the stem-like compartment over time. CAR Tscm cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR Tscm cells was driven primarily by tumor- and host-related factors. These findings establish CAR Tscm cells as a promising platform for next-generation CAR T cell therapies.

Samer Al Hadidi, Frits van Rhee, Larry D Anderson

Plasma cell leukemia (PCL) represents an exceptionally aggressive plasma cell malignancy defined by &#x2265;5% circulating plasma cells in peripheral blood of patients otherwise meeting diagnostic criteria for multiple myeloma (MM), per International Myeloma Working Group consensus. This ultra-high-risk disease exhibits distinctive clinical features including frequent extramedullary involvement, severe cytopenias, hypercalcemia, renal insufficiency, and/or significantly elevated &#x3b2;2-microglobulin and lactate dehydrogenase levels. The molecular landscape includes high-risk cytogenetic abnormalities and mutations that promote accelerated proliferation, apoptotic resistance, immune evasion, and bone marrow microenvironmental independence through dysregulated adhesion molecule and chemokine receptor expression. While autologous stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies improved historical outcomes, the therapeutic paradigm continues to evolve. Novel therapeutic approaches including B-cell maturation antigen (BCMA)-directed therapies (bispecific antibodies and chimeric antigen receptor T-cell therapy), GPRC5D-targeted therapy, and BCL-2 inhibition demonstrate promise in treating both primary and secondary PCL. Despite these advances, PCL remains inadequately studied, with treatment approaches predominantly extrapolated from MM trials where PCL patients have largely been excluded. This review synthesizes current evidence and presents illustrative clinical cases demonstrating practical treatment approaches, while highlighting critical knowledge gaps requiring dedicated prospective clinical trials to meaningfully improve outcomes in this challenging disease entity.

Kai-Yang Chen, Hoi-Chun Chan, Chi-Ming Chan

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis, inflammation, neurosensory abnormalities, and epithelial damage. Despite the availability of topical immunomodulators and procedural interventions, a substantial proportion of patients with moderate-to-severe or refractory DED experience persistent symptoms and inadequate ocular surface recovery. Stem cell-based therapies, particularly mesenchymal stem cells (MSCs) and MSC-derived exosomes, have emerged as regenerative and immunomodulatory strategies aimed at restoring epithelial integrity and tear film stability rather than providing solely symptomatic relief. We conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of stem cell and stem cell-derived therapies in human DED.

Haruko Kunitomi, Aye Myat Khaine, Radia Jamee et al.

eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5+ intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity.

Jos&#xe9; F&#xe1;bio Lana, Luyddy Pires, Alex Macedo et al.

Knee osteoarthritis (KOA) is a degenerative joint condition characterized by progressive cartilage deterioration and chronic pain, leading to functional impairment. Bone marrow-derived orthobiologics, such as bone marrow aspirate clot (BMA-clot) and bone marrow aspirate concentrate (BMAC), have emerged as promising regenerative therapies. Despite their growing clinical use, no randomized clinical trials to date have directly compared the efficacy and safety of these two approaches in patients with KOA, leaving a gap in the current evidence base. This study aimed to compare the efficacy and safety of intra-articularBMA-clot and BMAC in patients with moderate to severe KOA over a 12-month follow-up period. In this prospective, randomized, double-blind clinical trial, patients aged 50-80 years with Kellgren-Lawrence grade 3-4 KOA were enrolled. Participants received thr ee monthly intra-articular injections of eitherBMA-clot or BMAC. The primary outcome was functional improvement assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included pain reduction (Visual Analog Scale) and quality of life (Short Form-36, SF-36). Adverse events were monitored, and data were analysed using mixed-effectsmodels. Both treatments resulted in significant improvements in pain, function, and quality of life throughout the 12-month period. Clinical outcomes between the BMA-clot and BMAC groups were not statistically different. The incidence of adverse events was low, with no serious complications observed. Intra-articular administration of BMA-clot and BMAC appears to be safe and effective for the management of moderate to severe KOA, providing sustained symptom relief and functional gains over a 12-month period. Given its simpler preparation and lower cost, BMA-clot may represent a more accessible therapeutic option in clinical settings.

Guomei Su, Jiangyun Peng, Jingyun Quan et al.

National Institute on Aging (NIA)

Background: Stem cells are found in body tissues. They can regenerate into more of the same cells or become other types of cell. Researchers want to use stem cells from taste buds to try to make cells that secrete insulin. Taste buds are found mostly on the tip and sides of the tongue. Researchers also want to study if the number of taste buds and stem cells decrease as people age. They will remove small pieces of tongue tissue (about the size of a pen tip). The taste buds will grow back. It is hoped that studying taste bud stem cells can lead to new diabetes treatments. Objectives: To see if stem cells from taste buds can be isolated in humans. Eligibility: Healthy adults at least 18 years old Design: Participants will be screened with: * Medical history * Physical exam * Blood and urine tests * Tongue photograph and mouth inspection. Food coloring will be applied to the tongue. Participants will have 1 study visit. They will not eat or drink anything 8 hours before. * They will give blood and urine samples. * They will have a tongue biopsy. Vital signs will be checked. The inside of the mouth will be examined. The tongue may be cleaned. The tongue will be numbed. Five small pieces of tissue will be taken with a small scissor. Any bleeding will be blotted with cotton and should stop in minutes. * Participants will be monitored for about 30 minutes. They will get a snack or meal. * They will be told how to take care of the tongue for the rest of the day. Participants will be called a week later to see how the Status: RECRUITING Conditions: Diabetes

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

This is a First-in-Human, open-label, early dose-escalation clinical study to evaluate the safety and preliminary efficacy of GC511B CAR T cell injection in Adult with DLL3+ r/r SCLC trial participants. Phase: PHASE1 Status: RECRUITING Conditions: Relapsed/Refractory Small Cell Lung Cancer Interventions: GC511B CAR-T Cell Injection

C&#xe9;line Marigny, Ga&#xeb;lle Revet, Anne Berger et al.

Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains the cornerstone of the treatment of Duchenne Muscular Dystrophy (DMD), the disease-associated fibrosis can limit its efficacy. We thus assessed the effects of eliminating cardiac fibrosis of DMD by CAR-T cells targeting Fibroblast Activation Protein (FAP), a protein strongly expressed by activated fibroblasts.

Zhaorui Jin, Bo Yang, Siyuan Zhang et al.

Tooth loss remains a major unmet clinical challenge, and current prosthetic approaches cannot restore the biological complexity, sensory function, or regenerative capacity of natural teeth. Recent progress in stem cell biology, developmental engineering, and regenerative biomaterials has opened new possibilities for biological tooth regeneration. This review integrates advances across three major research domains that together define the current landscape of translational regenerative dentistry. First, we discuss stem cell-based, scaffold-guided strategies for tooth regeneration. These approaches combine dental and nondental stem cells, including DPSCs, SCAPs, PDLSCs, SHED, and iPSC-derived lineages, with bioactive materials such as HA/TCP ceramics, dentin-derived extracellular matrix scaffolds, and natural or synthetic polymers to promote odontogenic differentiation, vascularization, and periodontal attachment. Second, we summarize emerging tooth organoid and bioengineered tooth germ technologies that recapitulate epithelial-mesenchymal interactions and enable controlled reconstruction of dentin-pulp and periodontal compartments for modeling human odontogenesis. Third, we highlight molecular regulation-driven therapeutic strategies, focusing on the modulation of Wnt, BMP, FGF, TGF-&#x3b2;, and USAG-1 pathways to stimulate endogenous tooth regeneration and correct developmental defects. Despite marked progress, challenges remain, including stable neurovascular integration, optimization of stem cell-material crosstalk, precise control of spatiotemporal signaling, and long-term functional stability in vivo. Finally, we outline future directions involving smart biomaterials, gene- and protein-based molecular targeting, organoid-guided regeneration, and iPSC-enabled personalized therapies, which may further accelerate the clinical translation of stem cell-based tooth regeneration.

Yue Zhang, Mingxia Du, Yi-Han Wang et al.

Retinal organoids (ROs) derived from human pluripotent stem cells are crucial for modeling retinal development and disease. However, the functional electrophysiological maturation of photoreceptors within ROs remains poorly characterized. This study aimed to define the functional maturation timeline of photoreceptors in human embryonic stem cell (hESC)-derived ROs.

Jiawan Sun, Serena Noss, Corrine Smolen et al.

Disease-associated variants can lead to variable phenotypic outcomes in neurodevelopmental disorders, but the biological mechanisms underlying this variability remain poorly understood. Here, we develop a framework to investigate this phenomenon using the 16p12.1 deletion as a paradigm of variable expressivity. Using induced pluripotent stem cell models from affected families and CRISPR-edited lines with the 16p12.1 deletion, we find that the deletion and rare variants in the genetic background jointly influence chromatin accessibility and expression of neurodevelopmental genes. Cellular analyses identify family-specific phenotypes, including altered inhibitory neuron production and neural progenitor cell proliferation, which correlate with head-size variation. CRISPR activation of individual 16p12.1 genes variably rescue these defects by modulating key developmental signaling pathways. Integrative analyses further identify regulatory hubs, including transcription factors FOXG1 and JUN, as mediators of these effects. Our study provides a functional framework for investigating how individual genetic architectures contribute to phenotypic variability in neurodevelopmental disorders.

Christopher P Johnstone, Kasey S Love, Sneha R Kabaria et al.

Gene syntax-the order and arrangement of genes and their regulatory elements-shapes the dynamic coordination of both natural and synthetic gene circuits. Transcription at one locus perturbs the transcription of adjacent genes, but the molecular basis of this effect remains poorly understood. In this work, we show that supercoiling-mediated feedback arises from transcription and regulates expression of adjacent genes in a syntax-specific manner. Using a suite of assays, we measured syntax- and induction-dependent formation of chromatin structures in human induced pluripotent stem cells. Applying syntax as a design parameter, we built and improved compact gene circuits, tuning the expression mean, noise, and stoichiometry across delivery methods and cell types. Integrating supercoiling mediated feedback into models of gene regulation will expand our understanding of native and synthetic systems.

Marty G Yang, Hannah J Richter, Simai Wang et al.

Despite decades of biochemical and structural studies of the nucleosome1, researchers lack genome-scale methods to determine variability in nucleosome structure along individual chromatin fibres. To address this, here we present Iteratively Defined Lengths of Inaccessibility (IDLI), a computational method that maps the single-molecule co-occupancy of structurally distinct nucleosomes, subnucleosomes and other protein-DNA interactions through long-read single-molecule footprinting2,3. IDLI classifies methylase-inaccessible footprints on individual chromatin fibres into (i) linker-histone-associated nucleosomes; (ii) nucleosomes with focal DNA accessibility along the nucleosome wrap; (iii) unwrapped nucleosomes; and (iv) subnucleosomal species such as hexasomes, tetrasomes and other short DNA protections. Applying IDLI to chromatin from mouse embryonic stem cells, we discover that more than 85% of nucleosomes exhibit intranucleosomally accessible DNA (nucleosome 'distortion'). We observe epigenomic-domain- and expression-level-specific patterns of distortion, including at promoters and mouse satellite repeat sequences. Transcription factor (TF) motif occurrence correlates significantly with distinct types of distortion, and degron experiments provide evidence of direct regulation by TFs. We apply IDLI to in vitro endoderm differentiation in human induced pluripotent stem cells and primary mouse hepatocytes. In both cases, we observe distortion at pioneer TF FOXA2&#xa0;binding sites, demonstrating&#xa0;that distortion is developmentally encoded and present in vivo. Finally, genetic experiments in mice show that a nucleosome-binding domain of FOXA2 directly affects nucleosome structure in vivo, implicating these protein-nucleosome interactions as direct mediators of distortion. Our work suggests extreme but regulated nucleosome structural variability at the single-molecule level. Furthermore, our approach offers opportunities to model TF binding, nucleosome remodelling and cell-type-specific chromatin regulation across biological contexts.

Konstantina Nikolakopoulou, Weand Yba&#xf1;ez, Lh&#xe9;anna Klaeyl&#xe9; et al.

Menstruation is an unusual process in which the human endometrium undergoes cyclical shedding with scarless regeneration. Despite its pivotal role in reproductive health, the cellular states and interactions orchestrating this process remain poorly defined, largely due to the lack of in vitro systems that capture the inaccessible perimenstrual window. We use human endometrial organoids to establish an in vitro menstrual cycle (IVMC) protocol that recapitulates cyclical epithelial dynamics. We validate the IVMC by benchmarking against in vivo samples spanning the menstrual window through histology, transcriptomic, and multiplex secreted-protein analysis. During menstruation, the in vivo luminal epithelium acquires a distinct transcriptomic signature, characterized by WNT7A expression. Loss of WNT7A compromises long-term organoid survival, highlighting its functional importance. The regeneration-associated luminal epithelium acts as a signaling hub during regeneration through interactions with the vasculature. This work opens new avenues to dissect the unique regenerative program of the endometrium in health and disease.

Alberto Rossetti, Job Stoks, Roel L H M G Sp&#xe4;tjens et al.

Dipeptidyl aminopeptidase-like protein 6 (DPP6) is a subunit of the Kv4 channels that carry the transient-outward current (ito) in cardiac Purkinje cells (PCs) and ventricular myocytes (VMs). dpp6 genetic variants have been linked to severe arrhythmia syndromes. Given the influence of other ito subunits on the Nav1.5-mediated cardiac sodium current (ina), we examined whether DPP6 regulates both ito and ina. We explored the impact of the dpp6 missense variants c.821G>A and c.637C>T, segregating in families with long-QT syndrome (LQTS), and c.2252C>T and c.1578G>C, associated with J-wave syndromes (JWSs) and unexplained syncope. In human and mouse heart slices, DPP6 localized within 40 nanometers of Nav1.5. Functionally, DPP6 reduced ina and increased ito density in transfected Chinese hamster ovary cells. dpp6 variants linked to LQTS and JWSs led to a hypo- and hyperinhibition of ina, respectively. Conversely, ito was increased by the JWS variants and decreased by the LQTS variants coexpressed with PC (but not VM) ito subunits. These findings were validated in human induced pluripotent stem cell-derived cardiomyocytes. In silico modeling of ina and ito data into PC and VM single-cell action potentials, subsequently integrated in two-dimensional tissue simulations, produced steep repolarization gradients for LQTS-c.821G>A versus slowed conduction for JWS-c.2252C>T. Noninvasive electrocardiographic imaging, used for advanced clinical phenotyping, showed dispersed and prolonged repolarization in the dpp6 c.821G>A index patient versus right ventricular outflow tract delayed activation of a dpp6 c.2252C>T carrier. In conclusion, dpp6 variants play an important role in the mutually antagonistic regulation of ina and ito, contributing to cardiac electrophysiology and arrhythmogenesis.

Shuaibing Jiang, Guangyu Bao, Zhen Yang et al.

Blood clots are pivotal for haemostasis and regeneration1, but they are mechanically weak and form slowly2, posing risks for life-threatening haemorrhage and limiting broader applications3-5. These limitations are attributed to complex coagulation cascades, abundant mechanically ineffective cells and little structural polymers. Strategies that strengthen polymer networks are inapplicable to these highly cellularized materials. Here we report a strategy that rapidly crosslinks red blood cells into tough cytogels and integrates them within blood clots. The resulting engineered blood clots (EBCs) form within seconds and exhibit a 13-fold increase in fracture toughness, and a 4-fold improvement in adhesion energy compared with native clots. Experiments and modelling identify the rupture of mechanically integrated cells as a key toughening mechanism. In vivo studies demonstrate that EBCs can rapidly halt haemorrhage, promote tissue regeneration, mitigate inflammation and foreign body reactions, and prevent postoperative adhesion. The safety and efficacy of both autologous and allogeneic EBCs were also validated. Our strategy is applicable to a range of cells and polymers. This work may motivate the development and translation of highly cellularized materials for bleeding control, wound management, tissue repair and regenerative medicine.

Sean R Golinski, Karla Soriano, Alex C Briegel et al.

Dysfunction of the sodium-activated potassium channel Kna1.1 (encoded by KCNT1) is associated with a severe neurodevelopmental condition characterized by frequent seizures (up to hundreds per day), treatment resistance, and increased mortality during childhood. Yet, recent progress with an RNA therapy targeting KCNT1 offers clinical promise1. We characterize the early developmental onset of Kna1.1 channels in prenatal and neonatal brain tissue, establishing a timeline for pathophysiology and a window for therapeutic intervention. Using patch-clamp electrophysiology, we observe functional prenatal Kna1.1 conductance that is developmentally regulated. In excitatory and inhibitory neurons derived from a child's induced pluripotent stem cells with a KCNT1 pathogenic variant (p.R474H), we detect gain-of-function K+ currents. We use an antisense oligonucleotide RNA therapy developed for two individuals with the p.R474H variant-which results in dramatic reductions in seizure occurrence and severity1-to profile cellular neurophysiology in patient-derived excitatory and inhibitory neurons. We observe a knockdown of p.R474H gain-of-function K+ currents, resulting in a stimulation-dependent change in spiking output in patient-derived induced excitatory and inhibitory neurons. In mid-gestation primary human neurons, ASO knockdown suppresses current-evoked firing, suggesting a potential early therapeutic target before the onset of infantile encephalopathy.

Erika A Aguzzi, Stella Mary, Marzieh Mowlavi Vardanjani et al.

Optic neuropathies cause irreversible vision loss. Transplantation of pluripotent stem cell (PSC)-derived retinal ganglion cells (RGCs) offers one potential therapeutic avenue to restore vision in patients suffering from optic neuropathies if the donor neurons survive long term in the recipient eye and develop synaptic connections in the retinal inner plexiform layer (IPL) and subcortical visual centers, which has been difficult to achieve. Previous work in mouse retinal explant cultures has shown that enzymatic digestion of the retinal internal limiting membrane (ILM) promotes migration of transplanted RGCs into the recipient retina. Here, we examined donor RGC survival and engraftment in immunosuppressed mice, rats, and rhesus macaques and in postmortem human retinal explant cultures. Using three separate human PSC lines and three independent methods of ILM disruption (including enzymatic, developmental, and mechanical approaches), we demonstrated that the ILM is a barrier to retinal engraftment of intravitreally delivered human PSC-derived RGCs. Across models, ILM disruption was associated with greater donor RGC survival over 2 to 8 weeks and enabled migration of donor neuronal somata into the endogenous RGC layer, where they elaborated dendrites into the IPL and extended axons that followed the course of the endogenous retinal nerve fiber layer into the optic nerve head, findings that were negligible with intact ILM. Further, ILM disruption enabled donor RGCs to synaptically integrate into IPL circuits, conferring light responsivity in rodents. These findings have important implications for enabling neuronal replacement therapies to restore vision in patients with optic neuropathy.

Jiachen Li, Fan Yang, Ziyi Ren et al.

Adipose-derived mesenchymal stem cell conditioned medium (ADSC-CM) has emerged as a promising cell-free therapeutic strategy for acute lung injury (ALI). ADSC-CM's anti-inflammatory effect is closely related to its ability to regulate alveolar macrophage polarization. Furthermore, autophagy in macrophages is considered to be related to the regulation of polarization. However, the specific role and mechanisms by which ADSC-CM coordinates autophagy to guide macrophage polarization are not yet fully clear and urgently require further research.

Guorong Wang, Juntao Xu, Zhuo Chen et al.

Minghui Cao, Yingmei Tang, Yunhua Li et al.

Jillian M. Jespersen, Lia Avanesyan, Jean Publicover et al.

Chronic infection with hepatitis B virus (HBV) often leads to immune-mediated progressive liver injury and liver cancer. Seroclearance of the surface antigen (HBsAg) defines clinical cure and reduces disease-associated risks but rarely occurs. Here, we aimed to study the immune mechanisms of HBsAg clearance in chronic hepatitis B (CHB) using a mouse model of age-dependent HBsAg clearance and persistence and longitudinal peripheral blood samples from participants in the BeNEG-DO clinical trial who exhibited either HBsAg clearance or stable HBsAg level retention after stopping nucleos(t)ide analog therapy. Whereas HBsAg clearance in young mice failed and the ability to initiate and sustain HBV-specific CD4 + T cell responses in the liver was impaired, adult mice exhibited a robust HBV-specific CD4 + T cell response and HBsAg clearance. Depletion of CD4 + T cells in adult mice prevented HBsAg seroclearance and hepatocellular injury and disrupted hepatic leukocyte organization and HBV-specific CD8 + T cell cytotoxicity, whereas depletion of CD8 + T cells did not alter HBsAg seroclearance. Upstream of the CD4 + T cell response, hepatic myeloid cells, particularly type 2 conventional dendritic cells, directed CD4 + T cell priming and differentiation. Studies using samples from patients with CHB identified features of HBsAg clearance that overlapped with the mouse model, including T helper 1 and cytotoxic CD4 + T cell activation and augmented CD8 + T cell effector function. These findings identified a role for CD4 + T cell activation in the clinical cure of CHB and suggest that therapeutically enhancing CD4 + T cell responses could improve HBsAg clearance rates.

National Institute of Allergy and Infectious Diseases (NIAID)

Background: CGD causes infections and inflammation. The only cure currently is a bone marrow transplant. Most often a perfectly matched bone marrow donor is used. Researchers want to see if they can lower the risks of using a mismatched donor. Objectives: To see if it is safe to use a related bone marrow donor who is only a partial match to a person with CGD. To see how well drugs given to a person before and after transplant help the body accept the transplant. Eligibility: People ages 4-65 with CGD for whom stem cell transplant may be a cure and who do not have a perfectly matched donor, related or unrelated. Design: Participants will be screened with: Medical history Physical exam Blood tests Participants will be admitted to the hospital about 2 weeks before the transplant. They will have blood, urine, breathing, and heart tests. They may have CT and/or MRI scans. They will have a needle inserted into their hipbone to remove marrow. They will have dental, neurologic, and psychologic tests. They will have a central catheter placed: A line will be placed into a vein in their upper chest. They will get drugs, chemotherapy, and radiation to prepare for the transplant. Participants will receive the donated cells through their catheter. The cells will be from one of their relatives. Participants will stay in the hospital about 6 weeks after the transplant. After they leave the hospital, participants will have to stay in the area with visits about 2 times a week for approximately 100 days post transplant. Then visits will be every 3 to 6 months for 2 years. Then visits will be once a year. Phase: EARLY_PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Chronic Granulomatous Disease Interventions: Busulfan; Alemtuzumab; Cyclophosphamide; Sirolimus; Total Body Irradiation; Allogeneic peripheral blood stem cell

Affiliated Hospital to Academy of Military Medical Sciences

This is a single arm study to evaluate the safety and efficacy of Nanobody-Based CD19/CD20 Tandem Dual CAR-T-cell therapy for Relapsed/Refractory B-Cell Lymphoma Phase: EARLY_PHASE1 Status: NOT_YET_RECRUITING Conditions: Relapsed/Refractory B-Cell Lymphoma Interventions: CD19/CD20 Tandem Dual CAR-T

St. Jude Children's Research Hospital

To learn more about the long-term health in patients treated for B-Cell Acute Lymphoblastic Leukemia (B-ALL) with Cluster of Differentiation antigen 19 (CD19) -redirected chimeric antigen receptor (CAR) T-cells. Primary Objective: To evaluate the feasibility of conducting standardized clinical assessments of pediatric, adolescent and young adult (AYA) B-ALL survivors post CD19-CAR T-cell therapy, treated at multiple institutions, leveraging the St Jude Lifetime Cohort (SJLIFE) clinical and research infrastructure. Exploratory Objectives: * To describe the prevalence of persistent and new/late-onset health conditions developing ≥2-years post CD19-CAR T-cell therapy in survivors of pediatric and AYA B-ALL. * To characterize neurocognitive and neurologic function in survivors ≥2-years post CD19- CAR T-cell therapy. * To characterize immune health in survivors ≥2-years post CD19-CAR T-cell therapy. * To characterize functional status in survivors ≥2-years post CD19-CAR T-cell therapy. Status: RECRUITING Conditions: B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Dennis Gong, Jimmy A Guo, Jennifer Su et al.

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs and metastasizes despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy, but its basis has remained unclear. We hypothesized that NRP represents a regeneration program co-opted by tumors recovering from cytotoxic injury. NRP signatures were strongly enriched in normal pancreatic injury and regeneration, and NRP cancer cells co-expressed transcription factors involved in pancreatic development. Our data support cell-intrinsic contributions and implicate IL-1&#x3b2;-associated inflammatory signaling as a plausible microenvironmental driver of elevated NRP expression. To enable direct phenotypic comparison with other cancer cell states, we established isogenic mouse organoid overexpression models for transcription factors linked to NRP, classical, and basal-like states. Glis3 emerged as a key NRP-associated factor, promoting clonogenicity, tumor growth, and metastasis. These findings identify a clinically relevant developmental regeneration program that emerges in PDAC after treatment.

Seyed Amir Sadrzadeh, Maryam Ranjbar, Mohammad Javad Entezari Meybodi et al.

Diabetic foot ulcers (DFUs) are a severe complication of diabetes characterized by impaired healing driven by oxidative stress, chronic inflammation, reduced angiogenesis, and neuropathy, leading to high risks of infection and amputation. Current therapies remain insufficient, necessitating advanced regenerative approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential through immunomodulation, angiogenesis, and extracellular matrix remodeling; however, their clinical application is limited by poor survival and retention, as well as potential safety concerns. Increasing evidence indicates that MSC-derived exosomes play a central role in mediating these therapeutic effects via paracrine signaling, delivering bioactive cargos such as microRNAs, proteins, and cytokines that regulate immune responses, angiogenesis, and tissue regeneration with lower immunogenicity and improved stability compared to cell-based therapies. Injectable hydrogels have emerged as biomimetic platforms that not only enhance MSC viability and retention but also provide an optimal delivery system for exosomes by protecting them from degradation and enabling sustained, localized release within the wound microenvironment. The integration of MSC-derived exosomes with hydrogel systems represents a synergistic strategy that simultaneously addresses multiple pathological barriers in DFUs, including inflammation, oxidative stress, and impaired vascularization. This review highlights recent advances in hydrogel-based delivery systems for MSCs and, importantly, MSC-derived exosomes, with a particular emphasis on their combined therapeutic potential in diabetic wound healing. Furthermore, emerging smart and stimuli-responsive hydrogels are discussed as next-generation platforms for optimizing exosome delivery and improving clinical outcomes in DFUs.

Chao Wei, Jun Sun, Zhuoyan Liu et al.

Abstract Selective gene expression is pivotal in orchestrating human development. Specifically, trithorax group (TrxG) and polycomb group (PcG) components play crucial roles in transcriptional activation and repression of state-specific stem cell expression programs, yet the mechanisms underlying their selective genomic binding remain poorly understood. In this study, we report that the polycomb repressive complex 1 (PRC1) subunit RYBP co-localizes with TrxG component WDR5 and selectively enriches PcG component RING1B in condensates in murine embryonic stem cells (ESCs). RYBP deficiency impairs the genomic binding of WDR5 and RING1B. Further, STAT3 excludes RING1B binding at RYBP-associated transcriptionally active loci. Additionally, RYBP depletion attenuates WDR5-dependent activation of DNA repair gene expression and facilitates the transition of ESCs to 2-cell-like cells. Finally, RYBP depletion disrupts RING1B deposition at lineage-specific genes, promoting ESC differentiation towards mesendoderm fate. These findings uncover RYBP as a regulator of selective genomic binding of TrxG and PcG components, providing insights into their roles in cell fate determination during development.

Northwell Health

Gene therapy is a new possible treatment for the anemia of DBAS. Gene therapy will soon be available for patients with RPS19-mutated DBAS. This involves inserting the corrected RPS19 gene into the cells, leading to correction of the anemia. The application of gene therapy requires sufficient numbers of stem cells on which the correction can be performed. Stem cells must be mobilized (stimulated to move) from the bone marrow to the peripheral blood and then collected (also called 'harvested'). It is not known if patients with DBAS can mobilize enough stem cells into the peripheral blood to allow for the harvesting of sufficient numbers to permit genetic manipulation. It is important to demonstrate the ability to harvest an adequate number of stem cells before gene therapy can be tried in patients with DBAS. The purpose of this study is to determine if mobilization of stem cells from the bone marrow in patients with DBAS is enough to obtain the numbers of peripheral blood stem cells necessary for effective gene therapy. An actual harvest will not be done. Status: RECRUITING Conditions: Diamond Blackfan Anemia Interventions: Mobilization Regimen

City of Hope Medical Center

This early phase I trial tests the safety and side effects of allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine and how well it works in treating patients with high-risk acute lymphoblastic leukemia after a matched related donor (allogeneic) hematopoietic stem cell transplant (alloHSCT). Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood, in this study, the T cells are cytomegalovirus (CMV) specific. Then the gene for a special receptor that binds to a certain protein, CD19, on the patient's cancer cells is added to the CMV-specific T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Vaccines made from three CMV tumor associated antigens, may help the body build an effective immune response to kill cancer cells. Giving allogeneic CMV-specific CD19-CAR T cells plus CMV-MVA vaccine after matched related alloHSCT may be safe, tolerable, and/or effective in treating patients with high-risk acute lymphoblastic leukemia. Phase: EARLY_PHASE1 Status: RECRUITING Conditions: Acute Lymphoblastic Leukemia Interventions: Allogeneic Hematopoietic Stem Cell Transplantation; Anti-CD19-CAR CMV-specific T-lymphocytes; Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Computed Tomography; Echocardiography; Leukapheresis; Lumbar Puncture; Magnetic Resonance Imaging; Multi-peptide CMV-Modified Vaccinia Ankara Vaccine; Multigated Acquisition Scan; Positron Emission Tomography; Transplant Conditioning; X-Ray Imaging

Junming Tao, Xiaoning Qiu, Datian Fu et al.

Apelin-13 plays a critical role in promoting angiogenesis and regulating cellular metabolism. However, the short half-life of Apelin-13 in vivo limits its further applications. Stem cell transplantation has been widely applied in tissue regeneration, but the low survival rate of transplanted stem cells in vivo restricts its therapeutic efficacy. This study aims to combine Apelin-13 with stem cell transplantation to enhance the survival rate of transplanted stem cells and promote bone regeneration.

Tadashi Kato, Mayu Yamashita, Masahiro Yasuda et al.

Long-term peritoneal injury results in loss of mesothelial integrity and impaired ultrafiltration, limiting the durability of peritoneal dialysis. Because primary human peritoneal mesothelial cells (PMCs) are difficult to obtain and expand, regenerative strategies for restoring peritoneal function have remained limited.

Yuanxin Wei, Shan Kou, Lieyang Qin et al.

Pw1, a maternally imprinted gene, is expressed in various stem cell populations, underscoring its crucial roles in tissue development, maintenance, and regeneration. While our recent work has revealed its regulatory function in cardiac fibrosis following ischemic injury, whether PW1+ cells exhibit stem cell properties in the heart remains unclear.

Li Long, Ju Qiao, Liang Wang et al.

Owing to impaired glucose metabolism, the high-glucose microenvironment in diabetic patients disrupts a series of biological reactions that hinder the wound healing process, resulting in a significant cost to the health care system and an urgent need for new and advanced therapies.

Markus C. Doeser, Julia Raimann, Maren Beuke et al.

Abstract Background Developing regenerative therapies to restore kidney function in patients with progressive renal disease represents a major challenge for modern molecular nephrology. Kidney organoids, three-dimensional kidney-like structures, which can now be generated by the directed differentiation of human pluripotent stem cells, have emerged as a powerful tool to study kidney development, physiology, and mechanisms of renal disease in vitro. Ultimately, kidney organoids may serve as an experimental platform to unravel the pathomechanisms of renal fibrosis and to test regenerative treatment approaches targeting fibrotic kidney diseases. However, the fibrotic phenotype in kidney organoids and its utility as a disease model remain to be fully characterized. Methods Three-dimensional self-organizing kidney organoids containing nephrons and stromal cells were exposed to TGF-β1 cytokine to induce fibrotic remodeling. Organoids were analyzed by RNA sequencing and histology. Results Activation of TGF-β1 signaling in kidney organoids induced hallmarks of human kidney fibrosis, such as tubular atrophy, glomerulosclerosis, and interstitial fibrosis. RNA sequencing highlighted differential regulation of key pathways in kidney fibrosis: epithelial-to-mesenchymal transition, inflammation, metabolism, and JAK/STAT signaling. We identified candidate mediators of kidney fibrosis such as the JAK-STAT downstream target PIM1. Inhibition of PIM1 with the small molecule AZD1208 attenuated fibrosis development in the organoids. Conclusions Kidney organoids are an amenable system for modeling kidney fibrosis and may guide therapeutic discovery.

Shuangshuang Yang, Siyu Chen, Wenya Zhuang et al.

Jasmine C. L. Atay, Anders Toftegaard Boysen, Rikke Nørregaard

Shalini Dimri-Wagh, Swarnabh Bhattacharya, Gharam Yassen et al.

Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas et al.

Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Zhenguo Wu, Xiaohan Zou, Chen Chen et al.

Overwhelming cardiomyocyte death and excessive cardiac fibrosis post myocardial infarction (MI) collectively lead to heart failure and mortality. For treating this devastating disease, it is essential to eliminate fibrosis and reconstitute the damaged myocardium, yet effective strategies remain elusive. Here, we created pleiotropic chimeric antigen receptor-monocytes (pCAR-Mos), revitalizing the injured heart via synergistic fibrosis clearance and myocardial reconstitution. Specifically, we engineered monocytes to express fibroblast activation protein (FAP)-chimeric antigen receptor (CAR) and secrete the cardioregenerative protein Agrin. CAR-mediated phagocytosis of myofibroblasts, which was further enhanced by Agrin, significantly attenuated fibrotic scar formation. Moreover, Agrin secretion promoted cardiomyocyte regeneration, thereby facilitating replenishment of functional myocardium. Treatment with pCAR-Mos remodeled the cardiac fibrotic microenvironment and substantially restored cardiac function in MI mice. In sum, our findings confirmed that pCAR-Mos exerted potent phagocytic activity against profibrotic myofibroblasts while simultaneously enabling myocardial reconstitution, thereby providing a reversible treatment strategy for MI with broad application in other fibrotic diseases.

Marion Guillon, Margaux Brin, Elodie Gabet et al.

Rett syndrome arises from loss-of-function mutations in the X-linked chromatin regulator MECP2, yet the earliest molecular derailments in development are poorly defined. Using isogenic human embryonic stem cell (hESC) models carrying three patient-derived MECP2 mutations, we followed the transcriptome from pluripotency through neuroectoderm, neural stem/progenitor stages. Developmental stage dominated transcriptional variance, but mutants shared a secondary program enriched for synaptic-membrane and extracellular matrix genes. Single-cell/bulk profiling at the embryonic stem cell (ESC) stage revealed partial na&#xef;ve-like drift, marked by the up-regulation of the na&#xef;ve-enriched factor ZFP42/REX1 and related markers in MECP2-mutant lines. Among convergently dysregulated genes, the cortical determinant EMX1 showed an abnormal developmental trajectory, early repression followed by overshoot, and was consistently altered across independent Rett PSC models. Single-nucleus RNA-seq of cerebral organoids uncovered allele-specific yet convergent disturbances in cortical lineage allocation. These data chart a continuous developmental trajectory for MECP2-mutant cells and nominate na&#xef;ve-like drift and mis-timed EMX1 expression as tractable entry points for dissecting Rett pathogenesis.

Linqi Jin, Christian Park, Sunder Neelakantan et al.

Human heart development depends on tightly coordinated genetic programs and biomechanical cues, yet the underlying cell-microenvironment interactions remain poorly understood because the developing heart is difficult to study in utero and accurate experimental models are lacking. Recent advances in stem cell biology and three-dimensional (3D) bioprinting now allow the construction of human tissue analogues with defined structure and function. Here we show a perfusable 3D bioprinted model of the human embryonic heart tube composed of layered myocardium, cardiac jelly, and endocardium. Human induced pluripotent stem cell-derived cardiomyocytes and endothelial cells are cultured under controlled flow conditions, producing constructs with high cell viability, complete lumen endothelialization, progressive myocardial compaction, and coordinated tissue-level contraction. Single-cell transcriptomic analysis reveals that dynamic flow promotes cardiac maturation and lineage specification. This platform provides a human-relevant model to study early heart development, investigate congenital heart disease mechanisms, and evaluate emerging therapeutic strategies.

Poseida Therapeutics, Inc.

Phase 1 study comprised of open-label, dose escalation, multiple cohorts of P-BCMA-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed / refractory Multiple Myeloma (RRMM). Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Myeloma Interventions: P-BCMA-ALLO1 CAR-T cells; Rimiducid; Methotrexate

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Background: Hematopoietic stem cell transplant (HSCT) is a common treatment for many cancers and other illnesses. But many people who have HSCT go on to develop liver dysfunction. Researchers want to know more about how and why this happens. In this natural history study, they will try to learn what factors lead to liver dysfunction; how underlying liver disease may affect the results of HSCT; and how HSCT may contribute to liver dysfunction. Objective: To understand the links between HSCT and liver dysfunction. Eligibility: Adults aged 18 years or older and children 3 to 17 years who are being evaluated for HSCT. Design: This study involves 11 visits in 4 years. Most visits will be in the first year. Before and after their HSCT, participants will undergo these tests: Physical exam, including blood tests and a test of heart function. Participants will provide stool samples. Liver biopsies. Samples of liver tissue will be removed. This may be done either by inserting a needle through the right side of the chest, or with a thin tube threaded to the liver from a vein in the neck. Adult participants will undergo this procedure 2 times: once before the HSCT and once about a year later. Imaging scans. Participants will lie on a bed that moves into either a cylinder or a donut-shaped machine. Ultrasound. Participants will lie still. A probe that uses sound waves will be slid over their skin to get pictures of the liver. Fibroscan exam. This is like an ultrasound that uses a special probe to measure the toughness of the liver. ... Status: NOT_YET_RECRUITING Conditions: Hematopoietic Stem Cell Transplant

Nordic MDS Group

This study aims to develop highly sensitive methods for early detection of relapse based on the patients unique mutations. Initially, a mutational screen is being performed. Primers directed against these mutations will be constructed and presence of mutations will be followed in bone marrow and blood frequently after transplantation. Status: COMPLETED Conditions: MDS; SCT; MRD

Benjamin Y Lim, Carissa Chen, Anna Fredericks et al.

Retinoic acid (RA) is a key morphogen in human retinal development, activating transcriptional programs that drive retinal progenitor differentiation and photoreceptor development, ensuring proper spatial organisation within the neural retina, essential for vision. Despite its well-established role in retinal patterning, the concentration-dependent effects of RA on human retinal cell fate specification and the regional definition of the primate macula and peripheral retina remain poorly understood. Here, we show that temporal and dosage-dependant modulation of RA during human retinal organoid differentiation induces distinct changes in retinal cell abundance, maturation, and organisation. Single-cell transcriptomics and protein analysis reveal that RA dosage influences the relative abundance and maturation of photoreceptors and retinal interneurons. Spatial transcriptomics analyses demonstrates that low RA levels biases retinal organoids toward a macular-like regional identity, whereas high RA levels promotes peripheral-like development. Collectively, our findings emphasise the critical role of RA signalling in retinal maturation and regional specification. This study elucidates mechanisms involved in human retinal development and we anticipate that controlled RA modulation in retinal organoids provides a strategy to refine disease modelling of inherited retinal disorders and enhance the specific generation of photoreceptors suitable for transplantation and regenerative therapies.

Yi Wang, Rui Yan, Ling Mao et al.

Feline panleukopenia is an acute and highly contagious disease caused by feline panleukopenia virus (FPV). Conventional therapeutic approaches often yield suboptimal outcomes in managing leukopenia, which consequently contributes to its high mortality rate. Mesenchymal stem cells (MSCs) are a type of multipotent stem cell characterized by their multidirectional differentiation potential and immunomodulatory capabilities. Studies have shown that MSCs possess the potential to treat inflammatory and immune-mediated diseases, support and promote hematopoiesis, and facilitate tissue repair. Therefore, this study was to investigate the clinical efficacy of combining MSCs with feline panleukopenia monoclonal antibody to propose a potential treatment for FPV.

Nour Hassaan, Tobias Schmidt, Zackarias Söderlund et al.

Abstract Background The variable clinical outcomes of mesenchymal stromal cell (MSC)-based therapy in acute respiratory distress syndrome (ARDS) are attributed to a variety of factors, including host microenvironmental factors. Interleukin-1β (IL-1β) has been linked to the development and progression of ARDS, and we have previously found that IL-1β could be used to predict MSC activation in vitro. However, the exact mechanisms through which IL-1β alters the MSC function and its interaction with the host immune cells remains unknown. Therefore, the aim of this study was to assess how IL-1β alters MSC function, with a specific focus on MSC-neutrophil interaction. Methods Human bone marrow-derived MSCs were exposed to 20 ng/ml IL-1β for 1 or 24 h. Following exposure, MSCs were analyzed using bulk RNA sequencing and key secretome proteins were measured in their conditioned medium. A transwell culture system was used to evaluate the neutrophil recruitment capacity of IL-1β-exposed MSCs, with or without NF-kB inhibition. MSCs exposed to serum free medium were used as controls in all experiments. Results The sequencing data revealed that genes involved in response to biotic stimuli and immune response were altered in MSCs exposed to IL-1β compared to control cells. In particular, genes essential for neutrophil recruitment were significantly upregulated after IL-1β exposure. The functional in vitro studies further validated these results, demonstrating that MSCs exposed to IL-1β had a significantly higher neutrophil recruitment capacity compared to unstimulated MSCs. Finally, inhibition of the NF-kB pathway resulted in a significant decrease of the MSC’s capacity to recruit neutrophils to levels similar as to the unstimulated control MSCs. Conclusion These data provide mechanistic insight into how inflammatory factors present in the host microenvironment might affect the interaction between MSCs and immune cells. This further highlights the need to understand the MSC mode of action, and to map out how the MSC fate might change in different host environments after administration.

Yi Qi, Masahito Kawabori, Sho Yamaguchi et al.

Abstract Background Spinal cord injury results in profound neurological disability driven initially by primary mechanical damage and subsequently by secondary injury processes characterized by progressive neuroinflammation. Intravenous administration of human amniotic mesenchymal stem cells (MSC) has emerged as a promising therapeutic approach; however, the optimal timing of administration and its relationship to dynamic immune responses remain unclear. Methods A rat contusion model of spinal cord injury was used to evaluate the effects of intravenous MSC administration at three post-injury time points: days 1, 3, and 7. Functional and histological assessments were performed for each group. Systemic inflammatory responses were evaluated through blood analysis of neutrophil and macrophage counts, systemic inflammation index (SII), and plasma proteomics. Local immune responses were assessed by quantifying infiltrating immune cells within the injured spinal cord. Results The most substantial improvement in locomotor function was observed in the day-1 treatment group, followed by the day-7 group, whereas the day-3 group showed minimal benefit. The day-3 group also demonstrated a trend toward greater lesion length and increased macrophage infiltration 28 days after injury. MSC administration reduced SII in the day-1 and day-7 groups but not in the day-3 group, which instead showed an increased systemic inflammatory response. Analysis of spinal cord tissue demonstrated that MSC treatment on day-1 effectively reduced neutrophil infiltration, which peaks at this time point, while day-7 administration reduced macrophage infiltration during its peak phase. In contrast, MSC administration on day-3 failed to attenuate either neutrophil or macrophage accumulation. Plasma proteomic profiling revealed enhanced complement and coagulation pathway activation specifically on day-3. Conclusions The therapeutic efficacy of intravenously administered MSC is highly dependent on the timing of intervention. Optimal benefit is achieved when treatment coincides with peak activation of a dominant target immune cell population and avoids the peak of complement and coagulation signaling. These findings support a phase-matched therapeutic strategy to maximize MSC effectiveness following spinal cord injury.

Laura-Yvonne Gherghina, Jocelyn L Y Tang, Leo Otsuki et al.

Abstract Reactivation of quiescent neural stem cells (NSCs) in the central nervous system (CNS) is a tightly controlled process that generates new neurons and glia to maintain homeostasis or enable repair post-injury, but it remains unclear if reactivation of distinct NSC populations is coupled. Here, we discovered that NSC quiescence exit in Drosophila follows a hierarchical sequence, whereby activation of anterior stem cells in the brain lobes precedes and is required for the timely state-transition of more posterior NSCs in the ventral nerve cord. To achieve this, quiescent NSCs transiently activate neuronal genes. This transient neuronal state is temporary and specific to NSC dormancy, as neuronal genes are switched off after stem cells resume proliferation. Blocking neuronal firing in brain lobe neurons delays the onset of posterior NSC reactivation. Our results reveal long-range communication between quiescent NSCs to coordinate reactivation across the CNS, enabled by a transient, plastic neuron-like state that allows direct interaction with neuronal axons.

Carolina Balbi, Giulia A Vassalli-Sandal, Giuseppe Vassalli

Abstract Initially regarded as insignificant cellular waste, extracellular vesicles (EVs) are now recognized as key mediators of intercellular communication, capable of transferring bioactive molecules—such as proteins, nucleic acids, and small compounds—between cells. This function has positioned EVs as promising cell-free therapeutic agents with the potential to transform modern medicine. Stem and progenitor cells naturally release EVs that can replicate many of the therapeutic effects of cell transplantation, while avoiding the challenges associated with administering living cells. EVs derived from various cell sources—including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, stromal cells, cardiac progenitor cells, and endothelial progenitor cells—have shown therapeutic efficacy in preclinical models of ischemic heart disease. EVs’ translation into human trials in cardiac therapy has lagged behind, however, largely due to challenges related to EV production standardization, regulatory frameworks, and the demonstration of reproducible efficacy in human subjects. Nevertheless, recent milestones have been achieved with the successful completion of the phase I EV-AMI trial (Safety Evaluation of Intracoronary Infusion of EVs in Patients with Acute Myocardial Infarction, NCT04327635) and the enrollment of the first patient in the phase I SECRET-HF trial (Treatment of Non-ischemic Cardiomyopathies by Intravenous Extracellular Vesicles of Cardiovascular Progenitor Cells, NCT05774509). This concise review outlines the evolution of EVs from basic biological discovery to innovative therapeutic platforms, with particular emphasis on their potential applications in acute myocardial infarction. Remaining challenges for clinical translation, including manufacturing and regulatory hurdles, will also be discussed.

Chen Wang, Yi Pan, Ruochen Dong et al.

Abstract Leukaemic stem cells (LSCs) reside in protective bone marrow (BM) niches that promote therapeutic resistance and relapse. Here we characterized longitudinal BM niches supporting LSC survival, distinguishing the metaphysis from the central marrow. Quiescent LSCs preferentially localized to the metaphysis and exhibited reduced stemness and aggressiveness upon mobilization to the central marrow. Targeting DPP4 in acute myeloid leukaemia (AML) cells altered CXCL12 gradients at three spatial scales. Systemically, reversal of the BM–peripheral blood CXCL12 gradient confined AML cells within the BM. At the BM level, disruption of the metaphysis–central marrow gradient displaced LSCs from their protective niche. At the microscale, loss of the CXCL12 gradient between N-cadherin + stromal cells and the surrounding matrix impaired LSC recruitment. These effects arise from the CXCL12–DPP4–GPC3 axis, in which DPP4 truncates and inactivates CXCL12, whereas stromal GPC3 restrains DPP4 activity. Modulating this axis disrupts niche protection and enhances therapeutic vulnerability in AML.

University College, London

MAGNETO is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and teenagers aged 1-16 years with relapsed or refractory neuroblastoma. The study will assess the feasibility of generating the ATIMP (GD2 CAR T cells) and the safety of administering the ATIMP in patients with relapsed or refractory neuroblastoma. Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Neuroblastoma Interventions: GD2 CAR T cells

Shenzhen Geno-Immune Medical Institute

This is a Phase I/II clinical trial of gene therapy for treating Chronic Granulomatous Disease using a high-safety, high-efficiency, self-inactivating lentiviral vector TYF to functionally correct the defective gene. The objectives are to evaluate the safety and efficacy of the TYF-CGD gene transfer clinical protocol. Phase: NA Status: RECRUITING Conditions: Chronic Granulomatous Disease Interventions: Infusion of lentiviral TYF-CGD-modified autologous stem cells

National Cancer Institute (NCI)

Background: Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to the person. Researchers think adding the drug pembrolizumab might make the therapy more effective. Objective: To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma tumors. Eligibility: People ages 18-72 years with metastatic melanoma OF THE SKIN Design: Participants will be screened with: Physical exam CT, MRI, or PET scans X-rays Heart and lung function tests if indicated Blood and urine tests Before treatment, participants will have: A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white blood cells. The rest of the blood returns through a needle in the other arm. An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if assigned) Participants will stay in the hospital for treatment. This includes: Daily chemotherapy for 1 week For some participants, pembrolizumab infusion 1 day after chemotherapy TIL cell infusion 2-4 days after chemotherapy, then aldesleukin infusion every 8 hours for up to 12 doses Filgrastim injections to help restore your blood counts Recovery for 1-3 weeks After treatment, participants will: Take an antibiotic and an antiviral for at least 6 months, as applicable If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have another round. Have 2-day follow-up visits every 1-3 months for 1 year and then every 6 months Phase: PHASE2 Status: RECRUITING Conditions: Melanoma Interventions: young TIL; Pembrolizumab; Aldesleukin; Fludarabine; Cyclophosphamide

City of Hope Medical Center

This phase I trial tests the safety, side effects, and best dose of autologous anti-CD19 CAR-expressing T lymphocytes (CD19-CAR T cells) in older adults with B-cell acute lymphoblastic leukemia. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of B-cell acute lymphoblastic leukemia. Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: B Acute Lymphoblastic Leukemia Interventions: Autologous Anti-CD19 CAR-expressing T Lymphocytes; Biospecimen Collection; Bone Marrow Aspiration and Biopsy; Cyclophosphamide; Fludarabine; Leukapheresis; Questionnaire Administration

Cabaletta Bio

RESET-SSc: A Phase 1/2 Open-Label Study to Evaluate the Safety and Efficacy of CABA-201, a CD19-CAR T cell therapy, in Subjects with Systemic Sclerosis Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Systemic Sclerosis; Scleroderma Interventions: CABA-201

Shenzhen Geno-Immune Medical Institute

The purpose of this study is to assess the feasibility, safety and efficacy of mesenchymal stem cells (MSCs) in combination with CAR-T cells in treating autoimmune disease. Another goal of the study is to learn more about the safety and function of the MSCs combined with CAR-T cells and their long term effects in autoimmune disease patients. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Autoimmune Diseases Interventions: fetal MSCs combined with 4SCAR T cells

Sclnow Biotechnology Co., Ltd.

Evaluate the safety of human umbilical cord mesenchymal stem cells (hucMSCs) in POI treatment; Evaluate the effective hucMSCs in POI treatment. Compare different infusion mode, meanwhile compare with hormone replacement therapy (HRT) withdrawal, so that assessing the stem cell therapy. Phase: PHASE2 Status: SUSPENDED Conditions: Premature Ovarian Failure Interventions: hucMSCs

Sclnow Biotechnology Co., Ltd.

This is a randomized, double-blind study. Human umbilical cord mesenchymal stem cells (hUC-MSC) will be treated on cerebral infarction patients, and evaluates their neurological function of convalescent period. Phase: PHASE1, PHASE2 Status: SUSPENDED Conditions: Cerebral Infarction Interventions: Allogeneic umbilical cord mesenchymal stem cell; Aspirin Enteric-coated Tablets & Atorvastatin Calcium

Shenzhen Geno-Immune Medical Institute

This study will evaluate safety and efficacy of a combination of 4th generation chimeric antigen receptor gene-modified T cells targeting CD19 negative ALL that express CD22, CD123, CD38, CD10, CD20 and TSLPR, as many patients developed CD19-negative disease after CD19 CART immunotherapy. Clinical response and development of a standardized lentiviral vector and cell production protocol will be investigated. This is a phase I/II trial enrolling patients from multiple clinical centers. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Leukemia Interventions: 4SCAR-CD22/CD123/CD38/CD10/CD20/TSLPR

Jinliang He, Yang Liu, Lu Zhang et al.

Adipose-derived mesenchymal stem cell (ADMSC) exosomes have emerged as promising therapeutic agents for degenerative joint diseases, yet their molecular actions in knee osteoarthritis (KOA) remain inadequately defined. In this study, exosomes were isolated from ADMSCs under both physiological and IL-1&#x3b2;-induced inflammatory conditions and comprehensively characterized by NTA, TEM, and exosome marker expression. Both types of exosomes were efficiently internalized by chondrocytes, with uptake reaching saturation after 12&#x2009;hours regardless of inflammatory status. Functional assays revealed that while exosomes from healthy ADMSCs (EXOs) significantly enhanced levels of mitochondrial fusion proteins and decreased fission marker in IL-1&#x3b2;-induced chondrocytes after 24&#x2009;hours, these beneficial effects were absent in exosomes derived from inflamed ADMSCs (IL-1&#x3b2; EXOs). Notably, EXO treatment reduced intracellular ROS accumulation, boosted SOD2 levels, and diminished apoptotic cell rates in chondrocytes. In vivo, administration of EXOs to rats with ACLT-induced KOA markedly alleviated cartilage degeneration, restoration of mitochondrial dynamics, and suppression of inflammatory and matrix-degrading mediators. Transcriptomic analysis showed that EXOs activated gene expression programs related to fatty acid metabolism, oxidative phosphorylation, and AMPK signaling, while IL-1&#x3b2; EXOs enriched inflammatory and apoptotic pathways. Importantly, both genetic knockdown and pharmacological inhibition of AMPK abolished the restorative effects of EXOs on mitochondrial dynamics and on the reduction of apoptotic markers both ex vivo and in vivo. These findings demonstrate that exosomes secreted by ADMSCs preserve cartilage integrity in KOA via AMPK-mediated mitochondrial dynamics. This work supports AMPK-targeted modulation of mitochondrial dynamics by stem cell exosomes as a promising disease-modifying strategy for KOA.

Zihao Wang, Quhan Cheng, Mengxue Zhou et al.

Erythrocytes and erythrocyte membrane vesicles have shown promise for personalized drug delivery through passive immune evasion, yet their active role in immune phagocytosis remains largely unexplored. Here, we introduce a paradigm based on phosphatidylserine-everted erythrocyte membrane vesicles that trigger efferocytosis, enabling immune-mediated tissue regeneration rather than immune evasion. Incorporation of these phosphatidylserine-everted erythrocyte membrane vesicles into small-diameter vascular grafts markedly enhances endothelialization, suppresses calcification, and improves long-term patency in a rabbit carotid artery replacement model. Preclinical evaluation in a large canine model further demonstrates superior performance compared with clinically used expanded polytetrafluoroethylene grafts. This study establishes engineered phosphatidylserine-everted erythrocyte membrane vesicles as a versatile, customizable, and cost-effective biointerface for vascular grafts and other blood-contacting devices, providing a compelling strategy to harness innate immune mechanisms for regenerative medicine.

Muhammad Umair Mushtaq, John F. DiPersio, Jacques Azzi et al.

Abstract VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)–positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts ≥5%) at dose level 1 (DL1; 1 × 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 × 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 × 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell–associated neurotoxicity syndrome (1 ≥grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in arm A and 1 arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary antileukemic activity. This trial was registered at www.clinicaltrials.gov as #NCT05984199.

Li Chen, Lanyue Hu, Xiaofan Liu et al.

Abstract ANKRD26-related thrombocytopenia 2 (THC2) is a rare inherited platelet disorder caused by germ line variants in the 5′ untranslated region (UTR) of ANKRD26. Although prior studies using in vitro models or isolated case reports have suggested impaired megakaryopoiesis as a central mechanism, detailed insights have remained elusive, primarily due to the rarity, fragility, and heterogeneity of megakaryocytes (MKs). Here, we present a comprehensive, crossvalidated analysis of bone marrow samples from 4 independent patients with THC2, integrating single-cell transcriptomics and ex vivo functional profiling. Across all patients, we analyzed CD34+ hematopoietic stem and progenitor cells (HSPCs; 47 281 THC2 HSPCs vs 51 907 control cells) and primary MKs (pMKs; 7309 THC2 pMKs vs 5077 control cells), uncovering a consistent pattern of MK progenitors (MkP) expansion and a marked reduction in polyploid MKs, indicating a conserved pathophysiologic phenotype. In our index patient, we identified the 5′ UTR single-nucleotide variant in ANKRD26 that led to significantly elevated expression across 4 MK lineage subsets, spanning multipotent progenitors, common myeloid progenitors, MK-erythroid progenitors, and MkP as well as in terminally enriched pMKs. Confocal imaging localized ANKRD26 to the centrosome, implicating it in mitotic regulation during MK maturation. Mechanistically, we discovered that elevated ANKRD26 induces apoptosis in polyploid MKs via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis. This multipatient study provided the most comprehensive cellular and molecular portrait of ANKRD26-driven thrombocytopenia to date, offering novel insights into defective megakaryopoiesis and identifying candidate therapeutic targets to restore platelet production.

Kaiwen Zhao, Yuzhen He, Renqi Yao et al.

Audrey Belot, Andrew Rock, Sohini Dutt et al.

Heme, an iron-containing cofactor, is synthesized in mitochondria by an eight-enzyme pathway. Although cells were thought to manage heme autonomously, more than 1000 proteins contribute to its production, transport, and regulation. During terminal erythroid differentiation, mitochondria are discarded, yet hemoglobin production continues, which implies a cell-nonautonomous heme supply. We show that, under stress, erythroblasts import heme through the permease heme-responsive gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, the emergency program that expands red cell output. HRG1 loss impaired heme uptake, inhibited terminal erythroid differentiation, and caused anemia. In β-thalassemic mice, partial HRG1 loss reduces ineffective erythropoiesis, underscoring the importance of balanced heme import. These findings reveal intercellular heme sharing and identify HRG1 as a potential therapeutic target in hemoglobinopathies.

Sclnow Biotechnology Co., Ltd.

The purpose of this study is verify the safety and efficacy of Human Umbilical Cord Mesenchymal Stem Cells (UC-MSC) therapy for patients with Spinocerebellar Ataxia, and in addition, explore the possible mechanisms of UC-MSC therapy in Spinocerebellar Ataxia. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 6 Interventions: Intravenous infusion; Intrathecal injection; umbilical cord mesenchymal stem cell

Sclnow Biotechnology Co., Ltd.

1. Evaluation the safety of using human umbilical mesenchymal stem cells to treat patients with hepatitis B cirrhosis. 2. Observe the curative effect of patients with hepatitis B cirrhosis who use human umbilical mesenchymal stem cells to treat. 3. Explore the possible mechanism of human umbilical mesenchymal stem cells to treat patients with hepatitis B cirrhosis. Phase: PHASE1 Status: RECRUITING Conditions: Hepatitis B Interventions: Peripheral iv

Hope Biosciences Research Foundation

Methodology: Randomized, double-blind, efficacy and safety study of allogeneic HB-adMSCs vs placebo for the treatment of Crohn's Disease with a 16-week treatment period and a safety and efficacy follow up period for 52 weeks post first treatment. Treatment Duration: 16 weeks General Objectives: To assess the efficacy and safety of multiple intravenous infusions of allogeneic HB-adMSCs by improving signs and symptoms of Crohn's Disease in this subject population. Number of Subjects: 46 (23 in each treatment arm) Indication: Crohn's Disease Phase: PHASE2 Status: RECRUITING Conditions: Crohn Disease (CD) Interventions: HB-adMSCs - Hope Biosciences Adipose Derived Mesenchymal Stem Cells; 0.9% sodium chloride

LiangZou

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with refractory autoimmune diseases. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of CD19 CAR-T in the treatment of refractory autoimmune diseases. Phase: NA Status: RECRUITING Conditions: Autoimmune Diseases Interventions: JY231 (JY231 injection)

Ane Korff, Xiaojing Yang, Ozan Ozdemir et al.

Mutations in hnrnph2 cause an X-linked disorder characterized by developmental delay, intellectual disability, motor and gait disturbances, and seizures. Murine models that reproduce key clinical features of hnrnph2-related neurodevelopmental disorder suggest that it may result from a toxic gain of function of the mutant protein or a complex loss of normal HNRNPH2 function with impaired compensation by its paralog, HNRNPH1. In this study, we tested gapmer antisense oligonucleotides (ASOs) that target murine hnrnph2 in a non-allele-specific manner. The lead ASO reduced hnrnph2 messenger RNA (mRNA) and protein expression while inducing compensatory up-regulation of hnrnph1 expression in both wild-type and hnrnph2 mutant mouse brains. A single intracerebroventricular injection of the hnrnph2 ASO into neonatal mutant hnrnph2 mice rescued molecular and audiogenic seizure phenotypes and improved certain motor and cognitive phenotypes. ASO treatment at the juvenile stage also rescued audiogenic seizures. In contrast, hnrnph2 ASO administration did not alter survival, body weight, or the incidence of hydrocephalus. In human induced pluripotent stem cell-derived neurons, a human-specific hnrnph2 research ASO reduced hnrnph2 mRNA and up-regulated hnrnph1 mRNA. Mechanistically, we found that hnrnph1 expression is regulated by alternative splicing and that HNRNPH2 modulates this process. These findings provide a preclinical proof of concept for hnrnph2 ASO therapy and offer insights into its underlying molecular mechanism.

August Yue Huang, Zinan Zhou, Maya Talukdar et al.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000&#xd7;) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin. Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2, ASXL1, and DNMT3A variants. These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.

Qiutong Huang, M. Zeeshan Chaudhry, James Dight et al.

Abstract Natural killer cells defend against malignancies and viral infections through a tightly controlled program of differentiation and maturation. However, the transcriptional mechanisms guiding this process remain incompletely defined. Using paired single-cell multiomic profiling, we identify GFI1 as an epigenetic regulator of NK cell differentiation, coordinating EOMES and T-BET transcriptional balance to promote NK cell proliferation and the transition from immature to terminally differentiated NK cell states. GFI1 represses FOXO1 chromatin accessibility in mature NK cells, which normally limits NK cell proliferation and maturation. Co-deletion of both GFI1 and FOXO1 largely rescues NK cell differentiation, identifying a critical GFI1–FOXO1 axis required for protection against tumour metastasis. These findings position GFI1 as a key transcriptional node integrating NK cell differentiation, activation and effector programs.

Charles R. Crain, Aljawharah Alrubayyi, Itai Muzhingi et al.

Individuals who durably control HIV after cessation of antiretroviral therapy (ART) are of great interest for HIV cure efforts, but the correlates of posttreatment control remain incompletely understood. Here, we show across a diverse cohort of posttreatment controllers (PTCs), posttreatment noncontrollers (NCs), and spontaneous elite controllers (ECs) that robust expansion of HIV-specific CD8 + T cells and reduced viral reservoir diversity were strongly associated with durable (>1 year) viral suppression after ART cessation. In addition, HIV-specific CD8 + T cells in PTCs exhibited a stemlike memory phenotype, characterized by high TCF-1 (T cell factor 1) and low TOX (thymocyte selection–associated HMG box) expression, and readily differentiated into cytolytic effectors. Mapping of CD8 + T cell responses from PTCs revealed broad targeting of epitopes in a conserved autologous reservoir, whereas preferential targeting of epitopes derived from mutationally constrained regions was primarily a feature of CD8 + T cells from ECs. Univariable and additive analyses revealed a link between HIV-specific CD8 + T cell expansion, a stemlike phenotype, and conservation of human leukocyte antigen class I–restricted viral epitopes with posttreatment control. Together, these findings identify features of HIV-specific CD8 + T cells and the viral reservoir that are associated with sustained HIV control after ART cessation, informing future immunotherapeutic strategies toward achieving an HIV cure.

Alessandro Umbach, Annalisa Santini, Mattijs Bulcaen et al.

The 1717-1G>A is a prevalent splicing mutation causing cystic fibrosis (CF) for which no pharmacological treatments have been approved. This mutation disrupts a canonical 3′ AG splice acceptor site in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, leading to severe RNA missplicing, which prevents the correct synthesis of the encoded protein. In this study, we developed an adenine base editing (ABE) strategy to efficiently correct the 1717-1G>A mutation. By using the ABE9 base editor with the protospacer adjacent motif–relaxed Streptococcus pyogenes clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) variant SpRY, we obtained up to 30% editing with limited bystander effects in a human embryonic kidney (HEK) 293–based cellular model. Through systematic optimizations of the ABE system, delivered by electroporation of base editor messenger RNA (mRNA) and single guide RNA (sgRNA), we demonstrated genetic repair of the 1717-1G>A mutation in airway epithelial cells and intestinal organoids derived from people with CF. Functional analysis was performed by measuring short-circuit current in air-liquid interface (ALI) culture and by assessing forskolin-induced swelling (FIS) in intestinal organoids, which revealed restoration of CFTR channel activity. These results highlight SpRY-ABE9 as a potential genome editing strategy to permanently correct the CFTR 1717-1G>A mutation and restore CFTR function.

Oxford researchers found that while AI models like GPT-4 correctly diagnose medical conditions 94.9% of the time in isolation, real people using the same AI achieve less than 34.5% accuracy—no better than Google. The failure point isn't the AI's knowledge but the conversation itself, revealing a critical flaw in how medical chatbots are currently deployed.

Researchers discovered that the H3K27M mutation in deadly childhood brain tumors drives excessive lactate production, which directly activates DNA synthesis machinery through lactylation of the enzyme NME1. This finding enabled development of a deuterium-based MRI technique that can visualize tumor metabolism at clinical field strength and detect treatment response early—potentially transforming how we monitor these aggressive cancers.

Researchers tracked 34 cutaneous T-cell lymphoma patients using comprehensive multi-omics and serial sampling, creating the first single-cell resolution map of how cancer evolves to escape treatment. The study identified specific recurrent mutations — including STAT3 D661Y driving HDAC inhibitor resistance and EZH2 alterations targetable with existing drugs — providing a roadmap for genome-guided therapeutic decisions and improved disease monitoring.