title: Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.
abstract: GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal 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-mβgal vector infused systemically in adult GM1 mice (βGal(-/-)) at 1 × 10(11) or 3 × 10(11) vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal 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 × 10(11) vg dose revealed increased presence of βgal 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 × 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 βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan.
authors.affiliation: Department of Neurology, Gene Therapy Center.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Weismann
authors.affiliation: Department of Neurology, Gene Therapy Center.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Department of Neurology, Gene Therapy Center.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Keeler
authors.affiliation: Gene Therapy Center.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Microbiology and Physiological Systems.
authors.forename: Linghua
authors.initials: L
authors.lastname: Qui
authors.affiliation: Biochemistry and Molecular Pharmacology and Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Microbiology and Physiological Systems.
authors.forename: Zuoshang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Gene Therapy Center.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Neurology, Gene Therapy Center, miguel.esteves@umassmed.edu.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005732:Gangliosides / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*
chemical_list: D005732:Gangliosides; C061901:GLB1 protein, human; D001616:beta-Galactosidase