Engineered zinc finger repressors induce a prolonged and selective repression ofin nociceptors of nonhuman primates.

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 thegene, 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)gene. Adeno-associated virus (AAV)-mediated delivery of ZFRs in human induced pluripotent stem cell (iPSC)-derived neurons resulted in the reduction ofwith no detectable off-target activity. In the spared nerve injury (SNI) neuropathic pain mouse model, AAV-ZFR administration resulted in ≤70% repression ofin 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 ofin 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 ofin 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.