# Comparison of neonatal systemic and intracerebroventricular AAV9 gene therapy delivery demonstrating improved behavioral and phenotypic outcomes in a mouse model of Niemann-Pick disease, type C1

## TL;DR

This study compares different gene therapy delivery methods in a mouse model of Niemann-Pick disease, type C1, showing that early treatment improves survival and reduces disease symptoms.

## Contribution

The study demonstrates that neonatal systemic delivery of AAV9 gene therapy is as effective as intracerebroventricular delivery for treating NPC in mice.

## Key findings

- Neonatal systemic delivery of AAV9 gene therapy significantly improved survival and slowed disease progression.
- Both neonatal systemic and intracerebroventricular delivery achieved near-total Purkinje cell rescue.
- There was no difference in efficacy between the EF1α and Mecp2 promoters used in the study.

## 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.