Effects of adenovirus mediated GLA expression on gene expression of hiPSC-derived ventricular cardiomyocytes from control and Fabri Disease Lines

Fabry disease is an X-linked lysosomal storage disorder caused by loss-of-function mutations in GLA, resulting in α-galactosidase A deficiency and glycosphingolipid accumulation that contributes to systemic disease including kidney disease, stroke, and cardiac arrhythmias. To model Fabry-associated arrhythmogenesis, we generated hiPSC-derived ventricular cardiomyocytes (hiPSC-VCMs) from patient and control iPSCs and compared electrophysiology, calcium transients, and gene expression profiles between groups. Fabry hiPSC-VCMs displayed intrinsic chaotic arrhythmias and abnormal calcium handling along with dysregulated transcription of genes encoding ion channels. To assess the impact of restoring enzyme activity, both control and Fabry hiPSC-VCMs were infected with an adenovirus to drive GLA overexpression, and GLA restoration did not prevent complex arrhythmias or normalize ion-channel gene expression.