Duchenne muscular dystrophy (DMD) is a disabling genetic disease that causes the degeneration of skeletal muscles and premature death. The disease lacks a cure, and standard-of-care treatment with glucocorticoids can cause side effects such as obesity and mood disorders.
The researchers developed an improved preclinical model for testing alternative candidate therapies. The optimized protocol differentiates human induced pluripotent stem cells (iPSCs) to skeletal muscle fibers. First, cells from healthy adults are genetically reprogrammed into iPSCs, which are immature and can turn into multiple cell types.
Next, CRISPR-Cas9–mediated gene editing is used to introduce DMD mutations in the iPSCs, which are then exposed to a chemical cocktail to induce the formation of skeletal muscle cells.
The resulting cells are more mature than those generated by previously reported iPSC-based DMD approaches. As a result, the new DMD-mutant, iPSC-derived muscle fibers recapitulate major features of the disease.
For example, the mutant muscle fibers show excessive branching and fusion, contraction defects, and increased calcium signaling, when compared with nonmutant iPSC-derived muscle fibers.
Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion, and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are caused by antiinflammatory properties.
According to the authors, the preclinical model could be used to examine the molecular mechanisms underlying DMD, advance personalized medicine applications, and develop effective treatments with few side effects.
Improved stem cell model for Duchenne muscular dystrophy
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