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

Niemann-Pick disease, type C1 (NPC1) is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system (CNS) delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 weeks old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early- or late-stage of disease progression (4, 6 or 8 weeks old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced CNS transduction. In Npc1I1061T/I1061T mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-hNPC1 in pre-symptomatic disease states are likely to yield better outcomes in NPC1 individuals. Summary BlurbSystemic AAV9-hNPC1 gene therapy in null Npc1m1N mice at higher doses or with earlier administration and treatment of hypomorphic Npc1I1061T mice delays disease progression and increases lifespan.