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

Autor:	Davidson CD; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Gibson AL; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Gu T; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Baxter LL; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Deverman BE; Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA., Beadle K; Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA., Incao AA; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Rodriguez-Gil JL; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Fujiwara H; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Jiang X; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Chandler RJ; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Ory DS; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Gradinaru V; Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA., Venditti CP; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA venditti@mail.nih.gov., Pavan WJ; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA bpavan@mail.nih.gov.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2021 Aug 18; Vol. 4 (10). Date of Electronic Publication: 2021 Aug 18 (Print Publication: 2021).
DOI:	10.26508/lsa.202101040
Abstrakt:	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. (© 2021 Davidson et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu