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.

最近对非人类模型系统的研究显示了核苷修饰信使 RNA (modRNA) 治疗溶酶体贮积病的潜力。在这里，我们评估了 modRNA 治疗在诱导多能干细胞 (iPSC) 生成的人类心脏模型中恢复半乳糖苷酶 α ( GLA )（编码 α-半乳糖苷酶 A (α-GAL) 酶）表达的功效。来自两个患有法布里病的个体。与临床表型一致，来自法布里受影响个体的 iPSC 的心肌细胞显示鞘糖脂三酰神经酰胺 (GB3) 的积累，这是一种 α-半乳糖苷酶底物。此外，法布里心肌细胞表现出溶酶体相关蛋白的显着上调。经过GLA modRNA 处理后，一部分溶酶体蛋白部分恢复至野生型水平，这意味着与 Fabry 基因型相关的分子表型得到了拯救。重要的是，在GLA modRNA 处理的心肌细胞中观察到 GB3 水平显着降低，表明 α-GAL 酶活性得到恢复。总之，我们的结果验证了来自受影响个体的 iPSC 衍生心肌细胞作为研究法布里病疾病过程的模型的效用，以及GLA modRNA 治疗减少心脏中 GB3 积累的治疗潜力。