title: Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1.
abstract: Niemann-Pick disease, type C1 (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of NPC1 disease (Npc1-/-) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, ataxia, increased cholesterol storage, loss of cerebellar Purkinje neurons and early lethality. To test the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (AAV9) vectors to deliver the NPC1 gene under the transcriptional control of the neuronal-specific (CamKII) or a ubiquitous (EF1a) promoter. The Npc1-/- mice that received a single dose of AAV9-CamKII-NPC1 as neonates (2.6 × 1011GC) or at weaning (1.3 × 1012GC), and the mice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 × 1012GC), exhibited an increased life span, characterized by delayed weight loss and diminished motor decline. Cholesterol storage and Purkinje neuron loss were also reduced in the central nervous system of AAV9 treated Npc1-/- mice. Treatment with AAV9-EF1a-NPC1, as compared to AAV9-CamKII-NPC1, resulted in significantly increased survival (mean survival increased from 69 days to 166 and 97 days, respectively) and growth, and reduced hepatic-cholesterol accumulation. Our results provide the first demonstration that gene therapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the Npc1-/- mice after systemic AAV gene delivery.
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Randy J
authors: RJ
authors: Chandler
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Ian M
authors: IM
authors: Williams
authors: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Alana L
authors: AL
authors: Gibson
authors: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: Cristin D
authors: CD
authors: Davidson
authors: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Arturo A
authors: AA
authors: Incao
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Brandon T
authors: BT
authors: Hubbard
authors: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Forbes D
authors: FD
authors: Porter
authors: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: William J
authors: WJ
authors: Pavan
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors: Charles P
authors: CP
authors: Venditti
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D047908:Intracellular Signaling Peptides and Proteins; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000628:therapy*; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol