Nucleoside‐Modified mRNA Encoding Alpha‐Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC‐Derived Cardiomyocytes
Advanced Science, pp. e77151
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.
Authors 24
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Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine
Affiliation as printed
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine
Affiliation as printed
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover · Research Center for Translational Regenerative Medicine
Affiliation as printed
Center of Translational Regenerative Medicine Hannover Medical School Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Dean's Office for Academic Career Development nextGENERATION Medical Scientist Program Hannover Medical School Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine
Affiliation as printed
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology Hannover Medical School Hannover Germany
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Affiliation as printed
Proteomics, Institute of Theoretical Medicine Faculty of Medicine University of Augsburg Augsburg Germany
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Affiliation as printed
Proteomics, Institute of Theoretical Medicine Faculty of Medicine University of Augsburg Augsburg Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Cell Physiology Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Functional and Applied Anatomy Research Core Unit Electron Microscopy Hannover Medical School Hannover Germany
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Ivonne Jeanette Knorr Aachen Institute for Laboratory Animal Science and Experimental Surgery- Faculty of Medicine -
Affiliation as printed
Institute For Laboratory Animal Science and Experimental Surgery Faculty of Medicine RWTH Aachen University Aachen Germany
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Lisa Ernst Aachen Institute for Laboratory Animal Science and Experimental Surgery- Faculty of Medicine -
Affiliation as printed
Institute For Laboratory Animal Science and Experimental Surgery Faculty of Medicine RWTH Aachen University Aachen Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Department of General Visceral and Transplant Surgery Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Department of General Visceral and Transplant Surgery Hannover Medical School Hannover Germany
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Fraunhofer Institute for Toxicology and Experimental Medicine · Fraunhofer-Gesellschaft
Affiliation as printed
Fraunhofer Cluster of Excellence Immune‐Mediated Diseases Hannover Germany
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
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Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · Research Center for Translational Regenerative Medicine · Fraunhofer-Gesellschaft
Affiliation as printed
Center of Translational Regenerative Medicine Hannover Medical School Hannover Germany
Fraunhofer Cluster of Excellence Immune‐Mediated Diseases Hannover Germany
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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Thomas Thum corresponding
Medizinische Hochschule Hannover · Research Center for Translational Regenerative Medicine
Affiliation as printed
Center of Translational Regenerative Medicine Hannover Medical School Hannover Germany
Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
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