Systemic neonatal AAV9 gene therapy delivery improves behavioral and phenotypic outcomes comparable to intracerebroventricular delivery in a mouse model of Niemann-Pick disease, type C1

Abstract Niemann-Pick disease, type C (NPC), is an inherited fatal lysosomal storage disorder caused by a mutation in the NPC1 or NPC2 genes and characterized by impaired lysosomal cholesterol export. Previous studies have demonstrated that delivery of the NPC1 gene to the central nervous system (CNS) via an adeno-associated virus (AAV) can substantially improve lifespan and mitigate signs of disease in Npc1-deficient mouse models of NPC. To determine the optimal parameters for an efficacious AAV-based gene therapy for NPC, we measured the survival and disease phenotypes of mice treated systemically as neonates or at weaning age, along with neonatal mice treated via intracerebroventricular (ICV) delivery, with a construct containing either a ubiquitous truncated EF1α promoter or a truncated Mecp2 promoter. While all constructs and delivery methods resulted in improvement compared with baseline, mice treated as neonates survived significantly longer and experienced slower disease progression compared with those treated systemically at weaning age. Systemic delivery to neonates was capable of increasing survival and phenotypic improvement comparable to that of ICV delivery, and neonatal systemic and ICV delivery were both similarly capable of near-total Purkinje cell rescue. We also found no difference between a ubiquitous EF1α-derived promoter and an Mecp2-derived promoter. Ultimately, early treatment with maximal access to the CNS, whether via systemic or direct CNS delivery, is key to the efficacy of gene therapy in treating NPC. Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: The NIH has filed patents on behalf of WJP on work related to NPC1 genes and the AAV gene therapy treatment of NPC1 (US Patent Publication Numbers 20180104289, 20210113635). FO and JF are at present, or were during the time of their contribution to this manuscript, employed by Novartis Pharma AG and received salaries and own stock in Novartis as part of their remuneration for employment they have no competing interests as regards consultancies, patents or products in development or currently marketed. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.