Niemann-Pick type C2 (NPC2) disease is a rare, neurodegenerative disorder caused by mutations in the NPC2 gene, leading to lysosomal accumulation of unesterified cholesterol and other lipids. It is characterized by hepatosplenomegaly, liver dysfunction and severe neurological manifestations, resulting in early death. There is no effective therapy for NPC2 disease. Here, we evaluated the effectiveness of an adeno-associated virus (AAV), serotype rh.10 gene transfer vector expressing the mouse Npc2 gene (AAVrh.10-mNpc2-HA, HA tagged to facilitate analysis) to treat the disease in an Npc2-/- mouse model. A single intracisternal administration of the AAVrh.10-mNpc2-HA to 6 wk. old Npc2-/- mice mediated vector DNA, transgene mRNA and protein expression in brain and other organs. Compared to untreated Npc2-/- mice, AAV-treated Npc2-/- mice demonstrated amelioration of disease pathology in the brain, reduced lysosomal storage, reduced Purkinje cell death, decreased gliosis, and improved performance in behavioral tasks. Treatment-related reduction in serum disease markers was detected early and this effect persisted. Liver and spleen pathology were improved with significant reduction of liver cholesterol and sphingomyelin levels in treated Npc2-/- mice. Finally, administration of AAVrh.10-mNpc2-HA significantly extended life-span. Taken together, these data demonstrate the benefit of a one-time intracisternal administration of AAVrh.10-mNpc2-HA as a life-long treatment for NPC2 disease.
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