Beyond lysosomal storage: Correcting Fabry cardiomyocyte dysfunction with modified GLA mRNA

Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, resulting in deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and progressive accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3). Cardiac involvement is a major determinant of morbidity and mortality in Fabry disease. However, the cellular mechanisms linking the primary defect of α-Gal A deficiency and lysosomal storage to cardiomyocyte dysfunction remain incompletely understood.