200. Advancing a State of the Art Gene Therapy for Parkinson's Disease

Abstract

Niemann-Pick disease, type C1 disease (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. NPC1 commonly manifests in childhood, and there are no approved treatments to delay, stop, or reverse the fatal neurodegeneration that is the hallmark of this disorder. New therapies for patients with NPC1 need to be developed. Defects in the NPC1 gene are the cause of this disease. A murine model of NPC1, Npc nih (also called BALB/(cNctr-Npc1 m1N /J), arising from a spontaneous frame-shift mutation in the Npc1 gene has been described. Npc nih homozygotes (Npc1 -/-) have an early, severe, and rapidly progressing disease, which is characterized by weight loss, ataxia, and lethality by 9 weeks of age. To test the potential efficacy of gene therapy with the goal of developing a new treatment for NPC patients, we constructed an adeno-associated virus (AAV) serotype 9 to deliver the human NPC1 gene under the transcriptional control of the neuronal-specific promoter, mouse calcium/calmodulin-dependent protein kinase II (CaMKII). Npc1 -/mice received 1x10 12 GC of AAV9-CaMKII-NPC1 or an equivalent reporter control, AAV9-CaMKII-GFP, between 20 and 25 days of life delivered by retro-orbital injection. To achieve neuronal transduction, we relied upon the well-established property of AAV9 vectors to cross the blood-brain barrier and transduce neurons after systemic delivery. Relative to the untreated or AAV-GFP treated Npc1 -/mice (n=15, mean survival 66 days, SD=0.89), the Npc1 -/mice that received AAV9-CaMKII-NPC1 exhibited an increased life span (n=9, mean survival 105 days, SD=30; P<0.02) Although the AAV9-CaMKII-NPC1 treated Npc1 -/mice did not achieve a normal life expectancy or the same weight of wild-type mice, our results demonstrate, for the first time, the potential efficacy of systemic AAV gene therapy as a therapeutic option in patients with NPC1.