Genetic repair might treat Duchenne muscular dystrophy

A genetic technique that allows the body to work around a crucial mutation that causes Duchenne muscular dystrophy increased the mass and function of muscles in a small group of patients with the devastating disease, paving the way for larger clinical trials of the drug. The study in a handful of boys age 5 to 15 showed that patients receiving the highest level of the drug, called AVI-4658 or eteplirsen, had a significant increase in production of a missing protein and increases in muscle fibers. The study did not last long enough to show clinical improvement in the patients, but it demonstrated that the drug is safe in the short term and researchers are confident that longer-term trials, now in the planning stages, will show clinical benefit. “I’ve worked with patients with Duchenne muscular dystrophy for many years and this is the first time we can say with confidence that we’ve made a significant breakthrough towards finding a targeted treatment,” said Dr. Francesco Muntoni of the University College London Institute of Child Health, who led the study. Results were reported Sunday in the journal Lancet.

Duchenne muscular dystrophy affects about one in every 3,500 males worldwide. It is caused by any one of several different mutations that affect production of a protein called dystrophin, which is important for the production and maintenance of muscle fibers. Affected patients become unable to walk and must use a wheelchair by age 8 to 12. Deterioration continues through their teens and 20s, and the condition typically proves fatal as muscle failure impairs their ability to breathe.

Muntoni and his colleagues studied a variety of Duchenne muscular dystrophy in which affected boys are missing a fragment of the dystrophin gene called exon 51, a mutation that affects about 13% of such patients. The missing fragment converts exon 51 to a “stop” signal that halts the production of dystrophin, leading to a severely truncated protein that cannot carry out its normal function.

Two decades ago, pharmacologist Ryszard Kole of the University of North Carolina at Chapel Hill began exploring the use of a technique called antisense RNA to treat the condition. He used a specially prepared chain of ribonucleotides called an oligomer that binds to the mutated part of the gene, effectively hiding the stop signal from the cell’s protein-making machinery. The result is a slightly shorter form of dystrophin that is missing the portion normally coded for by exon 51. Despite the absence of that fragment, however, the dystrophin is functional. Kole took a leave of absence from the university and has been working at AVI Biopharma in Bellevue, Wash., to develop the treatment. That company produced the AVI-4658 used in the trial, and partially funded the trial.


Antisense technology can also be used to block the replication of viruses, and new drugs based on it are currently being tested against the ebola and Marburg viruses, as well as against hepatitis C.

“When I first tried my approach in a test tube some 20 years ago, a reviewer of my manuscript commented that it was ‘molecular gymnastics that would never amount to anything,’” Kole said in a statement. “Now we have evidence that it works and in an illness that has no other good therapeutic options.”

Muntoni and his colleagues gave the drug for 12 weeks in a variety of doses to 19 British boys. Seven of the boys responded to the drug, primarily those receiving the highest doses of the agent. At the beginning of the study, the boys, on average, were producing about 2% of the normal levels of dystrophin. After 12 weeks, six of them who received the highest dose were producing 18% of normal levels of dystrophin. No significant side effects were observed. The team believes that longer administration of AVI-4658 will raise the proportion much higher, and are now organizing blinded clinical trials of the drug.

In an editorial accompanying the report, two Japanese researchers noted that the barriers to scaling up the treatment are much lower than those for gene therapy because the targeted RNA is unlikely to affect other cells in the patients’ bodies. The approach might thus also be valuable for “developing treatments for other intractable hereditary neuromuscular disorders.”