Pathology
Permanent URI for this community
Pathology is part of the School of Medical Sciences.
Browse
Browsing Pathology by Author "Abu-Bonsrah, D."
Now showing 1 - 1 of 1
Results Per Page
Sort Options
Item Open Access GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals(Elsevier (Cell Press), 2023) 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.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.