ter Huurne, M.Parker, B.L.Liu, N.Q.Qian, E.L.Vivien, C.Karavendzas, K.Mills, R.J.Saville, J.T.Abu-Bonsrah, D.Wise, A.F.Hudson, J.E.Talbot, A.S.Finn, P.F.Martini, P.G.V.Fuller, M.Ricardo, S.D.Watt, K.I.Nicholls, K.M.Porrello, E.R.Elliott, D.A.2023-10-252023-10-252023American Journal of Human Genetics, 2023; 110(9):1600-16050002-92971537-6605https://hdl.handle.net/2440/139761Published: August 21, 2023Recent 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.en© 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Fabry DiseaseMyocytes, CardiacHumansFabry DiseaseRNARNA, MessengerInduced Pluripotent Stem CellsJournal article10.1016/j.ajhg.2023.07.0132023-10-24654682Saville, J.T. [0000-0002-1401-314X]Fuller, M. [0000-0001-9092-8942]