CRISPR Gene Editing Treatment for Duchenne Muscular Dystrophy Moves Closer to Clinical Trials

In the ongoing effort to develop new treatments for Duchenne muscular dystrophy (DMD), investigators say they have moved one step closer toward developing a new gene therapy for patients with the disease.

DMD is a disease occurring mostly in males which causes progressive weakness and the loss of skeletal and heart muscles. The telltale muscle weakness of the condition typically begins between 1 and 6 years of age in the hips, pelvic area, upper legs, and shoulders, and affects an estimated 1 in 5,000 boys. The root cause of DMD is a mutation in the DMD gene that is key to the production of a protein called dystrophin, which is produced in skeletal and heart muscle cells and works to stabilize and protect muscle fibers. Without dystrophin, patients experience muscle cell damage, and an inflammatory response creates further damage.

Recent advances in research on genetic editing and stem cell treatments for DMD using CRISPR gene editing technology have yielded some promising results, with some DMD therapies now in the clinical trial phase showing outstanding preliminary results. In a new study published on August 30, 2018, in the journal Science, investigators from the University of Texas Southwestern Medical Center report on the use of CRISPR to halt the progression of DMD in a large mammal, the first such study of its kind. In the study, the researcher team used a single-cut gene-editing technique to restore dystrophin in the muscle and heart tissue of canines, after previously correcting DMD mutations in mice and human cells.

Using the harmless adeno-associated virus to deliver CRISPR gene-editing components to an area of the dystrophin gene, the researchers tested their technique on 4 dogs. In an analysis at 6 weeks after intramuscular delivery or 8 weeks after systemic delivery, the study team observed restoration of the missing protein muscle tissue throughout the dogs’ bodies. Specifically, dystrophin was restored to levels ranging from 3% to 90% of normal depending on muscle type, and up to 92% of normal in the cardiac muscle of the dog that received the highest dose. In addition, the treated dogs showed improved muscle histology. The study authors say their findings establish the proof-of-concept for single-cut gene editing in dystrophic muscle and brings their treatment approach closer to the clinical trial phase.

“Our strategy is different from other therapeutic approaches for DMD because it edits the mutation that causes the disease and restores normal expression of the repaired dystrophin,” said the study’s lead author Leonela Amoasii, PhD, in a recent statement. “But we have more to do before we can use this clinically.”

The research team will next conduct longer-term studies in which they aim to measure the stability of dystrophin levels and look for adverse side effects, with the goal of moving to a clinical trial.