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

Authors: Makiko Yasuda, Marshall W. Huston, Silvère Pagant, Lin Gan, Susan S. Martin, Scott Sproul, Daniel A. Richards, Stephen J. Ballaron, Khaled Hettini, Annemarie Ledeboer, Lillian Falese, Liching Cao, Yanmei Lu, Michael C. Holmes, Kathleen Meyer, Robert J. Desnick, Thomas Wechsler - Molecular Therapy — Methods & Clinical Development 2020 cited by 55

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.