Nucleoside‐Modified mRNA Encoding Alpha‐Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC‐Derived Cardiomyocytes
11 affiliations
- 1Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
- 2Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
- 3Center of Translational Regenerative Medicine Hannover Medical School Hannover Germany
- 4Dean's Office for Academic Career Development nextGENERATION Medical Scientist Program Hannover Medical School Hannover Germany
- 5Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology Hannover Medical School Hannover Germany
- 6Proteomics, Institute of Theoretical Medicine Faculty of Medicine University of Augsburg Augsburg Germany
- 7Institute of Molecular and Cell Physiology Hannover Medical School Hannover Germany
- 8Institute of Functional and Applied Anatomy Research Core Unit Electron Microscopy Hannover Medical School Hannover Germany
- 9Institute For Laboratory Animal Science and Experimental Surgery Faculty of Medicine RWTH Aachen University Aachen Germany
- 10Department of General Visceral and Transplant Surgery Hannover Medical School Hannover Germany
- 11Fraunhofer 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.
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BibTeX
@article{juchem2026nucleosidemodified,
title = {{Nucleoside‐Modified mRNA Encoding Alpha‐Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC‐Derived Cardiomyocytes}},
author = {Malte Juchem and Lea Oehlsen and Sedef Ersoy and Jia Li Ye and Natalie Weber and Elisa Mohr and Wilson Agyapong and Junqing Liu and Maximilian Fuchs and Ke Xiao and Christopher Jahn and Reto Eggenschwiler and Tobias Cantz and Julia Beimdiek and Falk F. R. Buettner and Theresia Kraft and Jan Hegermann and Ivonne J. Knorr and Lisa Ernst and Linda Feldbrügge and Resa Puffert and Kevin Schmidt and Christian Bär and Jeannine Hoepfner and Thomas Thum},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77151},
url = {https://doi.org/10.1002/advs.77151},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nucleoside‐Modified mRNA Encoding Alpha‐Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC‐Derived Cardiomyocytes
AU - Malte Juchem
AU - Lea Oehlsen
AU - Sedef Ersoy
AU - Jia Li Ye
AU - Natalie Weber
AU - Elisa Mohr
AU - Wilson Agyapong
AU - Junqing Liu
AU - Maximilian Fuchs
AU - Ke Xiao
AU - Christopher Jahn
AU - Reto Eggenschwiler
AU - Tobias Cantz
AU - Julia Beimdiek
AU - Falk F. R. Buettner
AU - Theresia Kraft
AU - Jan Hegermann
AU - Ivonne J. Knorr
AU - Lisa Ernst
AU - Linda Feldbrügge
AU - Resa Puffert
AU - Kevin Schmidt
AU - Christian Bär
AU - Jeannine Hoepfner
AU - Thomas Thum
PY - 2026
DA - 2026/08/13
JO - Advanced Science
DO - 10.1002/advs.77151
UR - https://doi.org/10.1002/advs.77151
AB - 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.
SN - 2198-3844
ER -