Subretinal delivery of GMP-grade human neural progenitor cells protect vision in rat model of retinal degeneration and survive in minipigs

Abstract

Abstract Background: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. Methods: Research- grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rats, a rodent model for retinitis pigmentosa (RP); An IND-enabling study with CNS10-NPC was perform in the same rodent model; Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in large animal model-Yucatan minipig. Results: Both research grade hNPC and clinical-grade hNPC (termed CNS10-NPC) can survive and provide functional and morphological protection in a dose-dependent fashion in the RCS rats and defined the optimal cell dose used for an investigational new drug (IND) enabling study. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model-Yucatan minipig, which has eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. Conclusions: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.