PMID- 27798114
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20211204
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 26
IP  - 1
DP  - 2017 Jan 1
TI  - Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick 
      disease, type C1.
PG  - 52-64
LID - 10.1093/hmg/ddw367 [doi]
AB  - 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 x 1011GC) or at weaning (1.3 x 1012GC), and the 
      mice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 x 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.
CI  - Published by Oxford University Press 2016. This work is written by US Government 
      employees and is in the public domain in the US.
FAU - Chandler, Randy J
AU  - Chandler RJ
AD  - Medical Genomics and Metabolic Genetics Branch, National Human Genome Research 
      Institute, National Institutes of Health, Department of Health and Human 
      Services, Bethesda, MD, USA.
FAU - Williams, Ian M
AU  - Williams IM
AD  - Eunice Kennedy Shriver National Institute of Child Health and Human Development, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD, USA.
FAU - Gibson, Alana L
AU  - Gibson AL
AD  - Genetic Disease Research Branch, National Human Genome Research Institute, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD, USA.
FAU - Davidson, Cristin D
AU  - Davidson CD
AD  - Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, 
      Intellectual and Developmental Disabilities Research Center, Albert Einstein 
      College of Medicine, Bronx, NY, USA.
FAU - Incao, Arturo A
AU  - Incao AA
AD  - Genetic Disease Research Branch, National Human Genome Research Institute, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD, USA.
FAU - Hubbard, Brandon T
AU  - Hubbard BT
AD  - Medical Genomics and Metabolic Genetics Branch, National Human Genome Research 
      Institute, National Institutes of Health, Department of Health and Human 
      Services, Bethesda, MD, USA.
FAU - Porter, Forbes D
AU  - Porter FD
AD  - Eunice Kennedy Shriver National Institute of Child Health and Human Development, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD, USA.
FAU - Pavan, William J
AU  - Pavan WJ
AD  - Genetic Disease Research Branch, National Human Genome Research Institute, 
      National Institutes of Health, Department of Health and Human Services, Bethesda, 
      MD, USA.
FAU - Venditti, Charles P
AU  - Venditti CP
AD  - Medical Genomics and Metabolic Genetics Branch, National Human Genome Research 
      Institute, National Institutes of Health, Department of Health and Human 
      Services, Bethesda, MD, USA.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Niemann-Pick C1 Protein)
RN  - 0 (Npc1 protein, mouse)
RN  - 0 (Proteins)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Cerebellum/metabolism/pathology
MH  - Cholesterol/metabolism
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Female
MH  - *Genetic Therapy
MH  - Genetic Vectors/*administration & dosage
MH  - Intracellular Signaling Peptides and Proteins
MH  - Longevity/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Neurons/metabolism/pathology
MH  - Niemann-Pick C1 Protein
MH  - Niemann-Pick Disease, Type C/genetics/*therapy
MH  - Proteins/*genetics
MH  - Purkinje Cells/metabolism/pathology
PMC - PMC6075521
EDAT- 2016/11/01 06:00
MHDA- 2017/09/28 06:00
PMCR- 2016/10/25
CRDT- 2016/11/01 06:00
PHST- 2016/08/03 00:00 [received]
PHST- 2016/10/21 00:00 [accepted]
PHST- 2016/11/01 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2016/11/01 06:00 [entrez]
PHST- 2016/10/25 00:00 [pmc-release]
AID - ddw367 [pii]
AID - 10.1093/hmg/ddw367 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2017 Jan 1;26(1):52-64. doi: 10.1093/hmg/ddw367.