Journal Article Ahead of print
PubMed: 42591063 DOI: 10.1002/advs.77151
Nucleoside-Modified mRNA Encoding Alpha-Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC-Derived Cardiomyocytes.
Adv Sci (Weinh)
Authors: Malte Juchem, Lea Oehlsen, Sedef Ersoy, Jia Li Ye, Natalie Weber, Elisa Mohr, Wilson Agyapong, Junqing Liu, Maximilian Fuchs, Ke Xiao, Christopher Jahn, Reto Eggenschwiler, Tobias Cantz, Julia Beimdiek, Falk F R Buettner, Theresia Kraft, Jan Hegermann, Ivonne J Knorr, Lisa Ernst, Linda Feldbrügge, Resa Puffert, Kevin Schmidt, Christian Bär, Jeannine Hoepfner, Thomas Thum
Affiliations
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
- Center of Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
- Dean's Office for Academic Career Development, nextGENERATION Medical Scientist Program, Hannover Medical School, Hannover, Germany.
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
- Proteomics, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
- Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
- Institute of Functional and Applied Anatomy, Research Core Unit Electron Microscopy, Hannover Medical School, Hannover, Germany.
- Institute For Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany.
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, altered contractility, and enhanced calcium transient decay parameters. Mechanistically, phospholamban hyperphosphorylation may contribute to this calcium dysregulation. Consistently, modGLA therapy restored α-galactosidase A activity, reduced glycosphingolipid deposition, and normalized molecular alterations, including phospholamban hyperphosphorylation and calcium decay parameters, supporting modGLA as a promising therapeutic strategy for Fabry disease.
MeSH
Galactosidases, Alpha-Galactosidase, Biomedical Research, Heart, Phenotype, Rna, Messenger, Nucleosides, Calcium, Glycosphingolipids, Therapeutics, Cardiomyopathies, Fabry Disease, Myocytes, Cardiac, Phospholamban