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

DOI Web Site 被引用文献1件
  • Cristin D Davidson
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Alana L Gibson
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Tansy Gu
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Laura L Baxter
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Benjamin E Deverman
    Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA
  • Keith Beadle
    Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA
  • Arturo A Incao
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Jorge L Rodriguez-Gil
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Hideji Fujiwara
    Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
  • Xuntian Jiang
    Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
  • Randy J Chandler
    Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • Daniel S Ory
    Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
  • Viviana Gradinaru
    Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, USA
  • Charles P Venditti
    Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • William J Pavan
    Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

説明

<jats:p>Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in <jats:italic>NPC1</jats:italic>, 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 <jats:italic>Npc1</jats:italic><jats:sup><jats:italic>m1N/m1N</jats:italic></jats:sup> mice using an AAV-PHP.B vector ubiquitously expressing <jats:italic>NPC1</jats:italic> 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 <jats:italic>Npc1</jats:italic><jats:sup><jats:italic>m1N/m1N</jats:italic></jats:sup> mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor <jats:italic>Ly6a</jats:italic> in <jats:italic>Npc1</jats:italic><jats:sup><jats:italic>m1N/m1N</jats:italic></jats:sup> 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.</jats:p>

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