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iPSC-based Small Molecule Screening Reveals Possible Dysferlinopathy Treatment Approach

Review of “Phenotypic drug screening for dysferlinopathy using patient derived-iPS cells” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Mutations in the gene encoding the membrane protein Dysferlin causes progressive muscle disorders due to a lack of membrane repair after wounding [1]; however, patients with the W999C missense mutation display late onset of the disease [2], as the resultant misfolded protein retains some functionality but displays structural instability. Researchers from the laboratories of Yuko Kokubu and Hidetoshi Sakurai (CiRA, Kyoto University, Japan) hoped that inhibiting the degradation of misfolded dysferlin protein could prompt improvements in the dysferlinopathy phenotype. In their new STEM CELLS Translational Medicine study, the team recently combined the skeletal myocyte-directed differentiation of mutation carrying human induced pluripotent stem cells (hiPSCs) with a screen of small molecules to detect those with the ability to increase levels of dysferlin [3]. 

Kokubu et al. first established human iPSC from cells isolated from patients with the W999C missense mutation and induced skeletal myocyte differentiation via the forced expression of the skeletal muscle‐specific myogenic differentiation 1 (MyoD1) transcription factor [4, 5]. Subsequently, the authors evaluated around 600 well-known, off‐patent, Food and Drug Administration (FDA)‐approved drugs using an immunostaining‐based 384‐multiwell drug screening system, leading to the discovery of nocodazole treatment as an effective means to increase cellular dysferlin levels and enhance membrane resealing following injury by laser irradiation. 

Nocodazole has found use as an anticancer drug, due to its negative effect on microtubule formation and cell cycle arrest. In this study, the authors found that the disruption of the autophagy system following microtubule disorganization [6] mediated the increase in dysferlin levels rather than any effect on the proteasome degradation pathway, as the addition of the proteasome inhibitor MG‐132 alone failed to induce increased levels of dysferlin.

While the authors underline the difficulty in employing nocodazole itself for clinical purposes, they anticipate that their findings will provide new insight regarding possible targets for drugs against dysferlinopathy. Furthermore, they hope that their hiPSC-based screening platform will be combined with a large-scale small molecule library, thereby allowing the identification of safe and effective small molecule candidates for dysferlinopathy.

For more on using disease-specific hiPSCs and potential treatments for dysferlinopathies, stay tuned to the Stem Cells Portal!


  1. Bansal D, Miyake K, Vogel SS, et al., Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003;423:168-172.
  2. Takahashi T, Aoki M, Suzuki N, et al., Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B. Journal of Neurology, Neurosurgery & Psychiatry 2013;84:433.
  3. Kokubu Y, Nagino T, Sasa K, et al., Phenotypic Drug Screening for Dysferlinopathy Using Patient-Derived Induced Pluripotent Stem Cells. STEM CELLS Translational Medicine 2019;8:1017-1029.
  4. Davis RL, Weintraub H, and Lassar AB, Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987;51:987-1000.
  5. Tanaka A, Woltjen K, Miyake K, et al., Efficient and Reproducible Myogenic Differentiation from Human iPS Cells: Prospects for Modeling Miyoshi Myopathy In Vitro. PLOS ONE 2013;8:e61540.
  6. Mejillano MR, Shivanna BD, and Himes RH, Studies on the Nocodazole-Induced GTPase Activity of Tubulin. Archives of Biochemistry and Biophysics 1996;336:130-138.