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Nucleoside-Modified mRNA Encoding Alpha-Galactosidase A Ameliorates Fabry Disease Phenotypes in Human IPSC-Derived
Malte Juchem1,2, Lea Oehlsen1,2, Sedef Ersoy1
1Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 13, 2026
Summary
Fabry disease treatment using modGLA mRNA therapy shows promise. This approach effectively reduced glycosphingolipid buildup and corrected cellular defects in human heart cells, offering a potential new therapy for Fabry disease.
Area of Science:
- Biochemistry
- Genetics
- Cardiology
Background:
- Fabry disease is a lysosomal storage disorder caused by alpha-galactosidase A deficiency, leading to harmful glycosphingolipid accumulation.
- Current treatments for Fabry disease only delay progression and do not fully address the multi-systemic complications, particularly heart failure.
Purpose of the Study:
- To investigate the efficacy of systemic nucleoside-modified GLA mRNA (modGLA) therapy in human iPSC-derived cardiomyocytes modeling Fabry disease.
- To assess modGLA's ability to rescue cellular phenotypes of Fabry cardiomyopathy, including transcriptional dysregulation, apoptosis, and mitochondrial dysfunction.
Main Methods:
- Developed human iPSC-derived cardiomyocyte models for Fabry disease.
- Conducted transcriptomic and functional analyses to characterize disease phenotypes.
- Administered modGLA therapy and evaluated its impact on enzyme activity, glycosphingolipid levels, and cellular function.
Main Results:
- Fabry cardiomyocytes exhibited significant transcriptional dysregulation, apoptosis, mitochondrial dysfunction, and impaired calcium handling.
- modGLA therapy successfully restored alpha-galactosidase A activity and reduced glycosphingolipid deposition.
- modGLA normalized molecular alterations, including phospholamban hyperphosphorylation and calcium transient decay, rescuing cellular phenotypes.
Conclusions:
- modGLA therapy demonstrates significant potential for treating Fabry disease by addressing underlying molecular defects and cellular pathologies.
- This study validates modGLA as a promising therapeutic strategy for Fabry cardiomyopathy, particularly at the cellular level.
