Randy J. Chandler, Ian M. Williams, Alana L. Gibson, Cristin
D. Davidson, Arturo A. Incao, Brandon T. Hubbard, Forbes D. Porter, William J.
Pavan, and Charles P. Venditti. Systemic
AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type
C1. Hum. Mol. Genet. (2016) doi:
10.1093/hmg/ddw367 First published online: October 25, 2016
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.
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