TY - JOUR T1 - Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101040 VL - 4 IS - 10 SP - e202101040 AU - Cristin D Davidson AU - Alana L Gibson AU - Tansy Gu AU - Laura L Baxter AU - Benjamin E Deverman AU - Keith Beadle AU - Arturo A Incao AU - Jorge L Rodriguez-Gil AU - Hideji Fujiwara AU - Xuntian Jiang AU - Randy J Chandler AU - Daniel S Ory AU - Viviana Gradinaru AU - Charles P Venditti AU - William J Pavan Y1 - 2021/10/01 UR - https://www.life-science-alliance.org/content/4/10/e202101040.abstract N2 - 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 Npc1m1N/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 Npc1m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1m1N/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. ER -