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Gene transfer corrects acute GM2 gangliosidosis--potential therapeutic contribution of perivascular enzyme flow.

Published version
Peer-reviewed

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Type

Article

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Authors

Cachón-González, M Begoña 
Wang, Susan Z 
McNair, Rosamund 
Bradley, Josephine 
Lunn, David 

Abstract

The GM2 gangliosidoses are fatal lysosomal storage diseases principally affecting the brain. Absence of β-hexosaminidase A and B activities in the Sandhoff mouse causes neurological dysfunction and recapitulates the acute Tay-Sachs (TSD) and Sandhoff diseases (SD) in infants. Intracranial coinjection of recombinant adeno-associated viral vectors (rAAV), serotype 2/1, expressing human β-hexosaminidase α (HEXA) and β (HEXB) subunits into 1-month-old Sandhoff mice gave unprecedented survival to 2 years and prevented disease throughout the brain and spinal cord. Classical manifestations of disease, including spasticity-as opposed to tremor-ataxia-were resolved by localized gene transfer to the striatum or cerebellum, respectively. Abundant biosynthesis of β-hexosaminidase isozymes and their global distribution via axonal, perivascular, and cerebrospinal fluid (CSF) spaces, as well as diffusion, account for the sustained phenotypic rescue-long-term protein expression by transduced brain parenchyma, choroid plexus epithelium, and dorsal root ganglia neurons supplies the corrective enzyme. Prolonged survival permitted expression of cryptic disease in organs not accessed by intracranial vector delivery. We contend that infusion of rAAV into CSF space and intraparenchymal administration by convection-enhanced delivery at a few strategic sites will optimally treat neurodegeneration in many diseases affecting the nervous system.

Description

Keywords

Adenoviridae, Animals, Gangliosidoses, GM2, Genetic Vectors, Hexosaminidase A, Hexosaminidase B, Humans, Mice, Mice, Knockout

Journal Title

Molecular Therapy

Conference Name

Journal ISSN

1525-0024
1525-0024

Volume Title

20

Publisher

Cell Press
Sponsorship
We gratefully acknowledge support from The National Institute of Health Research-Biomedical Research Centre, an unrestricted grant from Cambridge in America, CLIMB (Children Living with Inherited Metabolic Disorders) National Tay–Sachs and Allied Diseases Association, MRC Link Programme Award, The Paul Morgan Trust and MRC core-funding (grant code U.1052.00.005).