Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan

UMMS Affiliation

Department of Neurology; Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Biochemistry and Molecular Pharmacology; Proteomics and Mass Spectrometry Facility; Wellstone Center for FSHD



Document Type



Genetics and Genomics | Molecular Biology | Molecular Genetics | Nervous System Diseases | Therapeutics


GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid beta-galactosidase (betagal) activity. betagal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mbetagal vector infused systemically in adult GM1 mice (betaGal(-/-)) at 1 x 10(11) or 3 x 10(11) vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high betaGal activity in liver and serum. Moderate betaGal levels throughout CNS resulted in a 36-76% reduction in GM1-ganglioside content in the brain and 75-86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 x 10(11) vg dose revealed increased presence of betagal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 x 10(11) vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316-576 days) was significantly increased over controls (250-264 days). This study shows that moderate widespread expression of betagal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan.

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Citation: Hum Mol Genet. 2015 Aug 1;24(15):4353-64. doi: 10.1093/hmg/ddv168. Epub 2015 May 10. Link to article on publisher's site

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