Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice.

ABSTRACT

Niemann-Pick disease, type C1 (NPC1) is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transport protein. There are no FDA approved treatments for this disorder. Both systemic and central nervous system delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose and window of therapeutic efficacy in Npc1 m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 weeks old and the medium dose at pre-, early, and post-symptomatic timepoints. Higher vector doses and treatment earlier in life were associated with enhanced transduction in the nervous system and resulted in significantly increased lifespan. Similar beneficial effects were noted after gene therapy in Npc1 I1061T mice, a model that recapitulates a common human hypomorphic variant. Our findings help define dose ranges, treatment ages, and efficacy in severe and hypomorphic models of NPC1 deficiency and suggest that earlier delivery of AAV9-hNPC1 in a pre-symptomatic disease state is likely to yield optimal outcomes in individuals with NPC1.