Engineered zinc finger repressors induce a prolonged and selective repression of scn9a in nociceptors of nonhuman primates.
Mohammad Samie, Toufan Parman, Mihika Jalan, Jisoo Lee, Patrick Dunn, Jason Eshleman, Dianna Baldwin Vidales, Kenneth Kennard, Josh Holter, Brian Jones, Yonghua Pan, Marina Falaleeva, Sarah Hinkley, Alicia Goodwin, Tammy Chen, Sumita Bhardwaj, Alex Ward, Michael Trias, Anthony Chikere, Madhura Som, Yanmei Lu, Sandeep Yadav, Jason Fontenot, Bryan Zeitler, Amy Pooler, Kathleen Meyer
Abstract
Peripheral neuropathies are estimated to affect several million patients in the US, with no long-lasting therapy currently available. In humans, the Nav1.7 sodium channel, encoded by the scn9a gene, is involved in a spectrum of inherited neuropathies and has emerged as a promising target for analgesic drug development. The development of a selective Nav1.7 inhibitor has been challenging, in part because of structural similarities with other Nav channels. Here, we present preclinical studies for a genomic medicine approach using engineered zinc finger repressors (ZFRs) specifically targeting the human/nonhuman primate (NHP) scn9a gene. Adeno-associated virus (AAV)-mediated delivery of ZFRs in human induced pluripotent stem cell (iPSC)-derived neurons resulted in the reduction of scn9a with no detectable off-target activity. In the spared nerve injury (SNI) neuropathic pain mouse model, AAV-ZFR administration resulted in ≤70% repression of scn9a in mouse dorsal root ganglia (DRGs) and was associated with reduction in pain hypersensitivity. AAV9-mediated intrathecal-lumbar (IT-lumbar) delivery of ZFRs in NHPs demonstrated repression of scn9a in bulk DRG tissue and single-cell levels in nociceptors 1 month after treatment. A lead AAV9-ZFR investigational product, ST-503, was developed and further evaluated in a 6-month study in NHPs. ST-503 administration by IT-lumbar infusion resulted in 50% repression of scn9a in bulk DRG tissue at 6 months without findings of dose-limiting toxicity or impact on neurological and cardiac safety pharmacology. Together, our results support further development of an AAV-delivered ZFR as a potential therapy for patients with peripheral neuropathies.