1. GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.
- Author
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Ter Huurne M, Parker BL, Liu NQ, Qian EL, Vivien C, Karavendzas K, Mills RJ, Saville JT, Abu-Bonsrah D, Wise AF, Hudson JE, Talbot AS, Finn PF, Martini PGV, Fuller M, Ricardo SD, Watt KI, Nicholls KM, Porrello ER, and Elliott DA
- Subjects
- Humans, Myocytes, Cardiac, RNA, RNA, Messenger, Induced Pluripotent Stem Cells, Fabry Disease genetics, Fabry Disease therapy
- Abstract
Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart., Competing Interests: Declaration of interests R.J.M., J.E.H., and E.R.P. are co-founders, scientific advisors, and hold equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. P.F. and P.G.V.M. are employees of and hold equity in Moderna., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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