making muscle wasting history

Dr. Ronald Cohn and his co-workers at the Johns Hopkins University School of Medicine in Baltimore are trying to modify the disease by blocking TGFβ and its signaling pathway that leads to fibrosis. They started their work with older mdx mice which have a more progressive muscular dystrophy than younger ones. Injection of the snake venom cardiotoxin into non-dystrophic single muscles damages them; they then regenerate within two to three weeks. In mdx muscles, this regeneration is significantly impaired. Treatment of mdx mice with an antibody against TGFβ improves the regeneration time.

As this antibody is not commercially available, the researchers started to test whether Losartan, an approved drug against high blood pressure, could have the same effect because it blocks the angiotensin-II receptor, which plays a role in a step further down in the signaling pathway that is initiated by TGFβ. Indeed, it could be shown that treatment of three-month old mdx mice with Losartan for more than one year attenuated many of their dystrophic symptoms like the fibrosis in the muscle and the development of fatigue in muscle function tests. The mice were not cured by this treatment, they were only less sick. Thus, treatment with Losartan, if results with Duchenne boys could be shown to be similar to those with mice, may be a therapeutic strategy similar to other pharmacological treatments that reduce the symptoms without influencing the genetic cause of the disease.

Dr. Cohn and his team are now preparing a doubleblind clinical trial of Losartan. About 100 Duchenne boys will participate who are between 5 and 15 years old and can still walk. One half of the boys will be treated for one year with Losartan. The other half will receive a placebo for six months and then for the next six month will also be treated with Losartan. All boys in both groups must continue to take steroids if they had taken them regularly before the trial. The primary outcome measure, that is the main test for an effect of the treatment, will be the time they need to walk for 30 feet (about 10 meters). Changes of their quality of life and their respiratory function will be among many other secondary outcome measures.

The researchers hope to start the trial sometime in 2008. The results will then be available about two years later. If the results show a significant therapeutic effect, a recommendation for taking the drug will be issued without delay. However, it is important to emphasize that until then, parents should not give Losartan to their sick boys, but should continue their current management including steroid treatment and all additional aspects to keep them in the best possible physical state.