Researchers use CRISPR to correct the mutation in the Duschenne muscular dystrophy model



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Duchenne muscular dystrophy (DMD) is a rare but devastating genetic disorder that causes muscle loss and physical impairment. Researchers at the University of Missouri's Faculty of Medicine have shown in a mouse study that the powerful gene-modifying technique called CRISPR could help fix the genetic mutation responsible for the disorder throughout life.

Children with DMD have a genetic mutation that interrupts the production of a protein called dystrophin. Without dystrophin, the muscle cells weaken and eventually die. Many children lose the ability to walk and the muscles essential for breathing and heart function eventually stop functioning.

"Research has shown that CRISPR can be used to suppress the mutation responsible for the early death of muscle cells in an animal model," said Dongsheng Duan, PhD, Margaret Proctor Mulligan, professor of medical research at the Department of Molecular Microbiology and D & Immunology of the MU School of Medicine and the lead author of the study. "However, relapses are a major concern because these muscle cells modified by the gene will wear over time.If we can correct the mutation in muscle stem cells, the cells regenerated from the modified stem cells will no longer carry the mutation.A timely treatment of muscle stem cells with CRISPR could result in continued expression of dystrophin in regenerated muscle cells. "

In collaboration with other UM colleagues and researchers from the National Center for the Advancement of Translational Sciences, the Johns Hopkins School of Medicine and Duke University, Duan reviewed if mouse muscle stem cells could be modified effectively. The researchers first delivered gene editing tools to normal mouse muscle via the AAV9 virus recently approved by the US Food and Drug Administration for treating spinal muscular atrophy.

"We grafted an AAV9-treated muscle on an immunodeficient mouse," said Michael Nance, a student in Duan's doctoral program in medicine and lead author of the article. "The grafted muscle is dead and then regenerated from its stem cells.If the stem cells have been successfully edited, the regenerated muscle cells should also carry the edited gene."

The reasoning of the researchers was correct, as they found many cells published in the regenerated muscle. They then tested whether muscle stem cells from a mouse model of DMD could be modified with CRISPR. Similar to what they found in normal muscle, the diseased muscle stem cells were also modified. Cells regenerated from these edited cells successfully produced dystrophin.

"This discovery suggests that CRISPR gene editing could provide a lifelong correction method for the genetic mutation of DMD and potentially other muscle diseases," said Duan. "Our research shows that CRISPR can be used to efficiently release stem cells responsible for muscle regeneration.The ability to treat stem cells responsible for maintaining muscle growth can pave the way for a unique treatment that can provide a source of modified cells. by the genes throughout the life of a patient ".

With more studies, researchers hope that this targeted CRISPR approach to stem cells could one day lead to sustainable therapies for children with DMD.

Reference: Nance et al. 2019. AAV9 modifies muscle stem cells in normal adult and dystrophic mice. Molecular Therapy. DOI: https://doi.org/10.1016/j.ymthe.2019.06.012.

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