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 delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1 m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 wk 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 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In Npc1 I1061T/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 presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.