Enhanced Efficacy of Gene Therapy Treatment for Niemann-Pick C1 Disease Using a Novel Serotype, AAV-PHP.B

Abstract

Accessing the central nervous system (CNS) continues to present a challenge when developing therapies for the treatment of neurological diseases. Overcoming the barrier of gene transfer to brains of animals and patients from systemic circulation has been difficult. Recent advances using Cre recombination-based adeno-associated virus (AAV) targeted evolution (CREATE) has yielded a promising new serotype, AAV-PHP.B, with greater transduction than AAV9 in the adult mouse CNS after systemic delivery. Here we show systemic delivery of a therapeutic AAV-PHP.B vector outperforms the naturally occurring AAV9 in treatment of a murine model of a rare lysosomal storage disorder, Niemann-Pick C1 (NPC1) disease. Approximately 95% of patients have a mutation in NPC1 which results in either absence or a significant reduction in functional NPC1, a lysosomal transmembrane protein involved in cholesterol transport. NPC1 pathology involves lysosomal accumulation of unesterified cholesterol and other lipids. Patients typically present with neurological symptoms and visceral complications including hepatosplenomegaly. Disease progression in the null mouse model of NPC1 (Npc1-/-) is characterized by weight loss, ataxia, and early death. Results: We previously reported that systemic delivery of an AAV9 vector expressing the human NPC1 gene under transcriptional control of a ubiquitous promoter (EF1a) improved lifespan and ameliorated disease phenotype of Npc1-/- mice. Using a similar study design, we find that an otherwise identical AAV-PHP.B vector improved lifespan in Npc1-/- mice more effectively than an AAV9 vector.