期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 110, 期 9, 页码 1600-1605出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2023.07.013
关键词
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This study evaluated the efficacy of nucleoside-modified messenger RNA (modRNA) treatment for Fabry disease and validated it using a human cardiac model generated from induced pluripotent stem cells. The results showed that modRNA treatment restored α-Galactosidase A enzyme activity and reduced glycosphingolipid accumulation, demonstrating its therapeutic potential.
Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treat-ments 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 a-Galactosidase A (a-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 a-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 mo-lecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that a-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.
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