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.

AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease

“…This would be more helpful to improve longevity. In addition, a very recent study reports that retro-orbital delivery of AAV9-based NPC1 expression under CamKII or EF1a promoters substantially increases the lifespan of NPC1 / mice (39). It will be interesting to compare the effects of various delivering routes, such as intracisternal (40), intracerebroventricular (41), or intracranial injections, on NPC1 expression in the CNS, as well as the reparative effects of AAV9-NPC1 on NPC1 phenotypes.…”

Changes in protein function underlies the disease spectrum in patients with CHIP mutations

“…Additionally, gene therapy approaches might be applicable to SCAR16. The obvious solution is to use gene editing approaches to correct these mutations; however, given the recessive nature of the disease, delivery of a functional copy of CHIP may also be beneficial (34,35); alternatively, antisense oligonucleotide therapy that can downregulate mutant CHIP protein levels may also prove to be an effective approach (36).…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…--SRT (Platt et al, 1997) (Sango et al, 1995) + + AAV (Sargeant et al, 2011;Cachon-Gonzalez et al, 2014), BMT (Norflus et al, 1998;Wada et al, 2000), CM (Pelled et al, 2003), Diet (Denny et al, 2010), HSP (Kirkegaard et al, 2016), MIP-1 (Wu and Proia, 2004), SRT (Jeyakumar et al, 1999) HexB ( Npc1 (−/−) (Morris et al, 1977) + -AAV (Chandler et al, 2017b;Xie et al, 2017;Hughes et al, 2018), AI (Alvarez et al, 2008), AO (Fu et al, 2013), CM (Erickson et al, 2000;Repa et al, 2007;Abi-Mosleh et al, 2009;Liu et al, 2010;Taylor et al, 2012;Hovakimyan et al, 2013;Nusca et al, 2014;Tanaka et al, 2014;Soga et al, 2015;Demais et al, 2016), Diet (Jelinek et al, 2015;Soga et al, 2015), HSP (Chung et al, 2016;Kirkegaard et al, 2016), NS (Griffin et al, 2004;Liao et al, 2009), Transplant (Veyron et al, 1996) Npc1 (Otterbach and Stoffel, 1995) + +…”

“…The I1061T mutant, which harbors the most common human NPC1 mutation, was generated to specifically study the effects of proteostatic modulation on disease progression. Various preclinical trials including GT, ERT, and transplant in these models have shown different but promising levels of success in prolonging mutant lifespan, reducing Purkinje cell atrophy and the storage phenotype (Veyron et al, 1996;Soga et al, 2015;Chandler et al, 2017b;Xie et al, 2017;Hughes et al, 2018).…”