An international team of researchers has successfully treated dogs with the canine form of Duchenne muscular dystrophy (DMD), a rapidly progressing and ultimately fatal muscle disease that afflicts one out of every 3,600 boys. The researchers used a novel technique called exon skipping to restore partial function to the gene involved in Duchenne. The study, published in Annals of Neurology, gives hope that a similar approach could work in humans.
DMD is caused by an aberration in the gene that encodes dystrophin, an important structural protein in muscle cells. Patients with DMD are unable to produce functional dystrophin, which leads to holes in the outer membranes of their muscle cells. Eventually, their muscles degenerate faster than they can be rebuilt, and few patients survive beyond their early 30s.
Unlike traditional gene therapy, which attempts to replace a mutated gene with a functional copy, exon skipping relies on a variation of a technique called antisense, in which short synthetic DNA or RNA molecules are designed to bind to a region of DNA or RNA and block its function. Companies are developing antisense therapies for cancer, diabetes, heart disease, and autoimmune diseases, among others.
The approach grew out of studies comparing DMD to a milder form of disease called Becker muscular dystrophy (BMD). Both diseases arise when patients are missing portions of the dystrophin gene’s exons, the areas of DNA that code for protein. Paradoxically, some BMD patients are missing much larger pieces of the gene yet are far healthier than patients with DMD. Several years ago, scientists found that the difference is not in how much of the gene is missing, but in how those missing portions affect the remaining gene sequence. Most Duchenne patients have frameshift mutations, which interfere with the cell’s reading of three-letter DNA code. These deletions shift the remaining DNA sequence into different triplet groupings, rendering the gene unreadable. In Becker patients, the remaining DNA can still be read normally, allowing them to produce a smaller but still functional version of dystrophin.
Eric Hoffman, a lead author of the study at Children’s National Medical Center, in Washington, DC, says that scientists realized they might help DMD patients by creating a “patch” that blocks transcription of a portion of the gene in a way that puts the remaining code back into sequence–essentially recreating the milder Becker muscular dystrophy.