Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice.

Viviana Gradinaru,Xuntian Jiang,Alana L Gibson,Benjamin E Deverman,Arturo A Incao,Keith Beadle,Tansy Gu,Randy J Chandler,Jorge L Rodriguez-Gil,Hideji Fujiwara,Daniel S Ory,Laura L Baxter,William J Pavan,Charles P Venditti,Cristin D Davidson

doi:10.26508/lsa.202101040

Abstract

Niemann-Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1 m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1 m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1 m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

Highlights

Niemann–Pick disease, type C (NPC) is a fatal, autosomal recessive lysosomal storage disorder with an estimated incidence of 1 in ~100,000 live births (Vanier, 2013)
Transduction efficacy of associated virus (AAV)-PHP.B versus AAV9 vectors was compared in Npc1m1N/m1N and Npc1+/+ mice treated with retroorbital injections of either an AAV-PHP.B-GFP or AAV9-GFP vector
These findings are consistent with previous studies that suggest greater central nervous system (CNS) transduction by AAVPHP.B vectors in comparison to AAV9 vectors, and these results demonstrate that the underlying disease state does not interfere with AAV-PHP.B CNS transduction

Summary

Introduction

Niemann–Pick disease, type C (NPC) is a fatal, autosomal recessive lysosomal storage disorder with an estimated incidence of 1 in ~100,000 live births (Vanier, 2013). In 95% of NPC patients, mutations in NPC1 (NPC1 disease, OMIM #257220), which encodes the NPC1 transmembrane protein found in the limiting lysosomal membrane (Carstea et al, 1997), is causative. The remaining 5% of patients have mutations in the soluble lysosomal protein NPC2 (NPC2 disease, OMIM #607625), which binds cholesterol and physically interacts with NPC1 (Naureckiene et al, 2000). NPC patients exhibit a wide array of neurological symptoms, including motor impairment and learning deficits, as well as visceral complications such as hepatosplenomegaly, with a highly heterogeneous disease severity and age of onset (Garver et al, 2007; Vanier, 2010; Patterson et al, 2013; Geberhiwot et al, 2018). There are no FDA-approved therapies for NPC in the United States, there is an urgent need for discovery of effective treatments for this debilitating, fatal disease

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Conclusion