Abstract P2120: Microdystrophin Design Comparisons In Dystrophin-Deficient Cardiomyocytes
| Autor: | Asuka Eguchi, Adriana Fernanda Gonzalez, Sofia Torres-Bigio, Sriram Bhimaraju, Foster Birnbaum, Helen M Blau |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Preclinical data show that smaller versions of dystrophin, called microdystrophins, can ameliorate disease progression. These transgenes, amenable to packaging into adeno-associated virus, have shown to be effective in improving skeletal muscle function; however, the functional benefit of microdystrophins in delaying heart failure is unknown. To identify the design principles that are important for addressing DMD heart dysfunction, three microdystrophin variants currently in clinical trials were tested in cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) with deficiencies in dystrophin. Previously, we reported that mechanical contraction and calcium handling are impaired in DMD iPSC-CMs. To test the functional benefit of the microdystrophins, we performed traction force microscopy, that provides multiparametric measurements of contraction, and calcium imaging with a ratiometric calcium-binding dye. Our results show a partial rescue of contractile deficits and aberrant calcium handling, underscoring the need for new design variants that address cardiomyocyte dysfunction. |
| Databáze: | OpenAIRE |
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