A research team from the University of Missouri School of Medicine has recently used CRISPR to edit a genetic mutation that contributes to Duchenne muscular dystrophy (DMD). This rare and debilitating genetic disorder is characterized by loss of muscle mass and physical impairment. By using this powerful gene-editing technology, these MU School of Medicine researchers have successfully treated mouse models of the disease. This work was published this summer in the journal Molecular Therapy.

Those with DMD possess a specific mutation that hinders the production of the dystrophin protein, which contributes to the structural integrity of muscle tissue. In the absence of this protein, the muscle cells weaken and eventually die. Pediatric patients with the condition often lose their ability to walk and can even lose the function of muscles that are essential for respiration and heart contractions.

Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model, explained senior author Dongsheng Duan, PhD, Margaret Proctor Mulligan Professor in Medical Research in the Department of Molecular Microbiology and Immunology at the MU School of Medicine. However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells.

Working alongside other researchers from MU, the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine and Duke University, Duan aimed to genetically modify muscle stem cells in mice. These scientists first edited the gene using an adeno-associated virus known as AAV9. Being this specific viral strain was recently approved by the FDA in treating spinal muscular atrophy, the researchers saw it as a viable candidate in treating DMD.

We transplanted AAV9 treated muscle into an immune-deficient mouse, said lead author Michael Nance, an MD-PhD program student in Duans lab. The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene.

Upon analyzing the regenerated muscle tissue, the researchers found that its cells contained the edited gene, supporting their reasoning. The team then tested whether the muscle stem cells in mice with DMD could be genetically edited using CRISPR. These findings also supported their hypothesis, with the stem cells in the diseased tissue sustaining these edits and the regenerated cells successfully producing dystrophin.

This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases, explained Duan. Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patients life.

Duan and colleagues hope that future research will help this stem cell CRISPR therapy become a revolutionary treatment for children with DMD.

Link:
Editing Muscle Stem Cells with CRISPR Treats Mouse Model of Muscular Dystrophy - DocWire News