Researchers at UT Southwestern Medical Center have developed a CRISPR technique to efficiently correct the function of heart cells in patients with Duchenne muscular dystrophy (DMD). It involves making a single cut at strategic points along patient's DNA, with the team claiming their new approach has the potential to correct most of the 3,000 mutations that cause DMD.

Duchenne muscular dystrophy (DMD) is one of nine neuromuscular disorders that affect the strength of muscles and nerves, specifically caused by defects in the gene that makes the dystrophin protein. Typically, one in every 3,500 boys born will be diagnosed with the disease at around three to four years of age, with their ability to walk gradually decreasing until they reach young adolescence. Most patients live until their 30s, but will require a wheelchair and respirator as the muscles in vital organs deteriorate over time.

Successfully tested in heart muscle cells, the method undertaken by Dr Eric Olson and his team offers an alternative to developing an individualized molecular treatment for the 3,000 mutations that cause DMD. By developing 12 guide RNAs to find mutation "hotspots" along the dystrophin gene, the Cas9 enzyme cut precisely at 12 designated sites while avoiding errant edits. Once the gene was successfully edited, it expressed an improved dystrophin protein product, rescuing cardiac function to near-normal levels.

From left to right: the beating function of a healthy heart muscle tissue, DMD heart muscle tissue, and tissue edited by CRISPR-Cas9(Credit: UT Southwestern)

"This is a significant step," says Dr. Eric Olson, Director of UT Southwestern's Hamon Center for Regenerative Science and Medicine. "We're hopeful this technique will eventually alleviate pain and suffering, perhaps even save the lives, of DMD patients who have a wide range of mutations and, unfortunately, have had no other treatment options to eliminate the underlying cause of the disease."

Building on previous CRISPR research carried out between 2014 and 2017, Dr Olson's procedure is less intrusive than traditional gene-editing techniques, and as such opens up possibilities for the same method to be applied to correct other single-gene mutations.

"This is a new concept," says Dr. Rhonda Bassel-Duby, co-author of the study and Professor of Molecular Biology at UT Southwestern. "Not only did we find a practical way of treating many mutations, we have developed a less disruptive method that skips over defective DNA instead of removing it. The genome is highly structured and you don't want to remove DNA that could potentially be important."

In further studies, researchers will continue to test their findings to ensure there are no severe side effects, as well as seek to improve the precision of the guide RNAs.

"This is a major advance," Dr. Bassel-Duby said. "Many different therapies have been put forward, but this one provides real hope to extend and improve the quality of patients' lives."

The study was published in Science Advances.

Source: UT Southwestern

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