Promising drug for Duchenne muscular dystrophy

By Dr. Ananya Mandal, MDJul 25 2011

Duchenne muscular dystrophy is a severely debilitating and lethal condition that affects 1 in 3,000. Females and males are affected, though females are rarely affected and are more often carriers. It is caused due to a defective gene that normally codes for the protein dystrophin, which helps provide a protective membrane around muscle fibers. Without this skin, muscle fibers become damaged and eventually die.

This mutation leads to a severe muscle-wasting condition which leads to difficulty walking, breathing and, often by their late teens the condition is so serious, it leads to an early death.

Now researchers are working on a small drug trial with 19 children. Early results are promising and show that it may be possible to safely reduce muscle degeneration by injecting tailored pieces of antisense RNA to removed the damaged piece of the genetic code and restore dystrophin production. The new drug takes the approach of “exon skipping,” or applying a tiny molecular patch over the deletion, so that the gene can produce a shorter but still functional version of the protein.

Initial results on muscle cells cultured in a lab dish and on mice showed promise after which the drug was tried on the children aged five to 15 at hospitals in London and Newcastle. Seven out the 19 showed a “significant” response, with levels of dystrophin rising to as much as 18 percent of normal levels. The volunteers, who were treated over 12 weeks, suffered no side effects. They did not show any major improvement in a standard six-minute walking test, although this was not the goal of the mini-trial. The drug, called AVI-4658, patches exon 51, which is deleted in about 15 percent of patients with DMD.

The study published online in the Lancet reads, “On the basis of our data and recent pre-clinical data, we expect that extended administration of AVI-4658 at doses of 10 mg/kilo or higher will result in sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration.” The next step is to test it for efficacy, say the researchers, led by Francesco Muntoni of the Dubowitz Neuromuscular Centre at UCL Institute of Child Health, London.

“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.

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.”