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Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 disease ( Npc1  -/- ) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, ataxia, increased cholesterol storage, loss of cerebellar Purkinje neurons and early lethality. To test the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver the  NPC1  gene under the transcriptional control of the neuronal-specific (CamKII) or a ubiquitous (EF1a) promoter. The  Npc1  -/-  mice that received a single dose of AAV9-CamKII-NPC1 as neonates (2.6 × 10 11 GC) or at weaning (1.3 × 10 12 GC), and the mice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 × 10 12 GC), exhibited an increased life span, characterized by delayed weight loss and diminished motor decline. Cholesterol storage and Purkinje neuron loss were also reduced in the central nervous system of AAV9 treated  Npc1  -/-  mice. Treatment with AAV9-EF1a-NPC1, as compared to AAV9-CamKII-NPC1, resulted in significantly increased survival (mean survival increased from 69 days to 166 and 97 days, respectively) and growth, and reduced hepatic-cholesterol accumulation. Our results provide the first demonstration that gene therapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the  Npc1  -/-  mice after systemic AAV gene delivery.

Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1