Duchenne muscular dystrophy (DMD) is a genetic disorder that causes degeneration in muscles and weakness. The disease comes from mutations in a gene that code for the dystrophin protein. The severity of the disease depends on the mutation. Now scientists at the University of Alberta have developed a potential therapy that might help as many as half of DMD patients by patching those errors. The treatment uses a cocktail of molecules that are similar to DNA, and they help produce functional dystrophin protein, restoring strength to muscles.
"In muscle, if there is no dystrophin there is no support of muscle membrane, and the muscle cells will become easily damaged or destroyed," explained Toshifumi Yokota, a professor of medical genetics at the University of Alberta. "Our DNA-like molecules restore the production of dystrophin so it can support the muscle cell membrane. Theoretically, this treatment could treat as many as 47 percent of patients with Duchenne muscular dystrophy."
In this work, the researchers used a molecule called an antisense oligonucleotide - a short stretch of single-stranded genetic material that is usually made to be complementary to some RNA sequence. Reporting in Molecular Therapy, Yokota’s team used a mix of them to create a kind of DNA stitch that can repair the gene mutations carried by DMD patients.
They were aiming to produce a shorter but still functional dystrophin protein by fixing mutations that cause a frameshift and make a very short and aberrant protein. After applying the antisense oligonucleotide mix to human muscle cells derived from patients, and a rodent model, they saw that the oligonucleotide cocktail was doing the job. It created a functional dystrophin protein.
While this approach has been attempted and has been approved by the FDA since 2016, the drug (eteplirsen) only applies to around 13 percent of patients. The cocktails used by Yokata’s team can be modified so they work on more patients - potentially half of those affected. The treatment may also significantly improve the quality of life for DMD patients, who have trouble walking and breathing as they get older. Many die in their 20s or 30s. Learn more about DMD from the video.
"Our treatment produces a shorter dystrophin protein than the drug being used now. This shorter protein is associated with extremely mild symptoms in some of the muscular dystrophy patients. Some have almost no symptoms at all," explained Yokota.
Now the investigators want to streamline the process and reduce the number of molecules used so that they can get to a clinical trial faster.