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AAV2/6 Gene Therapy in a Murine Model of Fabry Disease Results in Supraphysiological Enzyme Activity and Effective Substrate Reduction.

Authors :
Yasuda M
Huston MW
Pagant S
Gan L
St Martin S
Sproul S
Richards D
Ballaron S
Hettini K
Ledeboer A
Falese L
Cao L
Lu Y
Holmes MC
Meyer K
Desnick RJ
Wechsler T
Source :
Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Jul 09; Vol. 18, pp. 607-619. Date of Electronic Publication: 2020 Jul 09 (Print Publication: 2020).
Publication Year :
2020

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A ( GLA ) gene, which encodes the exogalactosyl hydrolase, alpha-galactosidase A (α-Gal A). Deficient α-Gal A activity results in the progressive, systemic accumulation of its substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), leading to renal, cardiac, and/or cerebrovascular disease and early demise. The current standard treatment for Fabry disease is enzyme replacement therapy, which necessitates lifelong biweekly infusions of recombinant enzyme. A more long-lasting treatment would benefit Fabry patients. Here, a gene therapy approach using an episomal adeno-associated viral 2/6 (AAV2/6) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette was evaluated in a Fabry mouse model that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues. A detailed 3-month pharmacology and toxicology study showed that administration of a clinical-scale-manufactured AAV2/6 vector resulted in markedly increased plasma and tissue α-Gal A activities, and essentially normalized Gb3 and Lyso-Gb3 at key sites of pathology. Further optimization of vector design identified the clinical lead vector, ST-920, which produced several-fold higher plasma and tissue α-Gal A activity levels with a good safety profile. Together, these studies provide the basis for the clinical development of ST-920.<br /> (© 2020 The Authors.)

Details

Language :
English
ISSN :
2329-0501
Volume :
18
Database :
MEDLINE
Journal :
Molecular therapy. Methods & clinical development
Publication Type :
Academic Journal
Accession number :
32775495
Full Text :
https://doi.org/10.1016/j.omtm.2020.07.002