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