Phenotypic Drug Screening for Dysferlinopathy Using Patient‐Derived Induced Pluripotent Stem Cells

Dysferlinopathy is a progressive muscle disorder that includes limb‐girdle muscular dystrophy type 2B and Miyoshi myopathy (MM). It is caused by mutations in the dysferlin (DYSF) gene, whose function is to reseal the muscular membrane. Treatment with proteasome inhibitor MG‐132 has been shown to increase misfolded dysferlin in fibroblasts, allowing them to recover their membrane resealing function. Here, we developed a screening system based on myocytes from MM patient‐derived induced pluripotent stem cells. According to the screening, nocodazole was found to effectively increase the level of dysferlin in cells, which, in turn, enhanced membrane resealing following injury by laser irradiation. Moreover, the increase was due to microtubule disorganization and involved autophagy rather than the proteasome degradation pathway. These findings suggest that increasing the amount of misfolded dysferlin using small molecules could represent an effective future clinical treatment for dysferlinopathy. Stem Cells Translational Medicine 2019;8:1017–1029 A phenotypic drug screening in a human pluripotent stem cell model of dysferlinopathy was performed. Nocodazole was identified as a compound that increased dysferlin protein levels. Such increase led to improved membrane resealing function.