Nucleoside-Modified mRNA Encoding Alpha-Galactosidase A Reverses Fabry Disease Phenotypes in Human IPSC-Derived Cardiomyocytes

Abstract The lysosomal storage disorder Fabry disease results from α-galactosidase A deficiency, leading to excessive glycosphingolipid substrate accumulation, primarily globotriaosylceramide (Gb3). While the underlying molecular mechanisms remain elusive, multi-systemic complications ultimately culminate in premature death, with heart failure being the leading cause of death. Current treatment options fail to treat Fabry disease adequately and only delay its progression. Preclinical studies on an alternative approach, systemic delivery of nucleoside-modified GLA mRNA (modGLA), suggest improved effectiveness over existing therapies in reducing glycosphingolipid levels in the heart. It remains unclear whether modGLA can rescue Fabry cardiomyopathy phenotypes at the cellular level, which are not faithfully recapitulated in current animal models. To address this, we investigated characteristic phenotypes in two new models of Fabry cardiomyopathy utilizing human iPSC-derived cardiomyocytes in transcriptomic and functional analyses. These human Fabry disease cardiomyocytes displayed broad transcriptional dysregulation, apoptosis, mitochondrial dysfunction, impaired reactive oxygen species handling, as well as enhanced decay parameters of calcium transients. Mechanistically, we identified hyperphosphorylated phospholamban as a major player in this calcium dysregulation. Strikingly, modGLA therapy of Fabry cardiomyocytes restored α-galactosidase A enzyme activity, reduced glycosphingolipid deposition, and normalized the observed molecular alterations, supporting modGLA therapy as a promising strategy for the treatment of Fabry disease. Competing Interest Statement TT is the founder and Chief Scientific/Medical Officer of Cardior Pharmaceuticals GmbH, which operates as a fully owned subsidiary of Novo Nordisk A/S Europe (not related to this publication). TT and CB are listed inventors on patents concerning the therapeutic application of RNAs, which have been licensed (unrelated to the work presented here). All other authors report no competing interests.