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

• DOI: 10.26508/lsa.202101040
• Publication Date: 2021-08-18T17:46:08Z
• Authors: Cristin D Davidson; Alana L Gibson; Tansy Gu; Laura L Baxter; Benjamin E Deverman; Keith Beadle; Arturo A Incao; Jorge L Rodriguez...; Hideji Fujiwara; Xuntian Jiang; Randy J Chandler; Daniel S Ory; Viviana Gradinaru; Charles P Venditti; William J Pavan
• Keywords: NPC1; Transduction (biophysics); Adeno-associated virus; Niemann–Pick disease; Lysosomal storage disease

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