Early Experiments in Treating Muscular Dystrophy With iPSC-based Gene Therapy Shows Promise

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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shutterstock_99471170A new study entitled “Precise Correction of the Dystrophin Gene in Duchenne Muscular Dystrophy Patient Induced Pluripotent Stem Cells by TALEN and CRISPR-Cas9” reports an iPSC-based gene therapy that can correct the genetic defect underlying Duchenne Muscular Dystrophy. The study was published in the journal Stem Cell Reports.

Duchenne muscular dystrophy (DMD) is a form of muscular dystrophy that is caused by a mutation of the Dystrophin gene, located in the X chromosome. Dystrophin protein is an essential component of muscle tissue. Its loss or deficiency leads to muscle degeneration, mainly in the muscle of legs and pelvis, but it progresses to other muscles, including the cardiac muscle. Currently, there is no cure for the disease.

In this study, a team of researchers at the Center for iPS Cell Research and Application (CiRA), Kyoto University hypothesized that using two genomic editing techniques – TALEN and CRISPR – they could correct the mutation in the Dystrophin gene. The nucleases in these techniques allow the editing of the genome by cutting genomic sequences at specific locations. However, this editing process is not without errors, and so its safety has to be determined before it can be used as a therapeutic in clinics.

To test this, the authors used induced pluripotent stem cells (iPS cells) from a DMD patient to optimize the experiment conditions to result in minimal off-target effects. The researchers tested three different correction methods — exon skipping, frameshifting, and exon knock-in — in the DMD-patient-derived iPSCs and discovered one of the methods, exon knock-in was efficient in correcting the dystrophin gene defect. Once they differentiated the corrected iPSCs in skeletal muscle cells, they could recover a functional dystrophin protein expression.

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The authors highlight that their results lay the foundation for the development of iPSC-based gene therapy for genetic disorders.

Lisa Li, study first author noted, “We show that TALEN and CRISPR can be used to correct the mutation of the DMD gene. I want to apply the nucleases to correct mutations for other genetic-based diseases like point mutations,” which will form the basis for next steps in further developing this therapeutic approach.