Drug may repair DMD heart damage
failure associated with the genetic disease, Duchenne muscular
dystrophy (DMD). The study is the first to demonstrate a new,
promising approach to repairing the cardiac damage inflicted.
Many sufferers of DMD die in their 20s from heart failure caused by cardiomyopathy, a gradual weakening of the heart muscle. While the mutation in the dystrophin gene primarily causes the progressive deterioration of skeletal muscles seen in people with MD, the mutation also affects cardiac muscle too.
Scientists at the University of Michigan (U-M) Medical School have been experimenting with a common chemical that is used in the pharmaceutical industry. Polyaxamer 188, a chemical sealant, has been involved in trials that have revealed the chemical can insert itself into small holes in cell membranes.
The study shows what happens to heart muscle cells (myocytes) in the absence of dystrophin. The study's authors emphasise, however, that several years of additional animal research will be required before the treatment could be tested in human patients.
According to Joseph Metzger, the university scientist who directed the research, Poloxamer 188, "assists the heart to be more compliant during the relaxation phase - allowing more blood to flow into the heart."
"We demonstrated this effect at the level of individual heart muscle cells, and it turned out to be true at the organ level, also," he added.
The key to the U-M discovery was technology invented by Soichiro Yasuda, a post-doctoral fellow and co-first author of the study. He created a device to allow the simultaneous measurement of force and intracellular calcium concentration in individual myocytes as they are stretched.
"We found that myocytes from normal mice easily handled a 20 per cent stretch in length, while myocytes from dystrophin-deficient or mdx mice had about 70 per cent more passive tension in response to the stretch."
"Compared to normal myocytes, mdx myocytes were stiffer and resistant to stretching. When they were stretched repeatedly, they started shaking and eventually contracted and died," he added.
The test is physiologically relevant as it mimics what happens in the heart muscle when myocytes relax and stretch to make room for incoming blood filling the heart. The test also shows the effect of a deficit of dystrophin on individual cardiac myocytes.
The stretching creates small tears or holes in the myocyte membrane allowing calcium ions to get inside the cell. When calcium floods a cell, it triggers a hyper-contraction, which causes the cell to die.
To test for the presence of tears in myocyte membranes, U-M researchers used a special fluorescent dye, which cannot penetrate an intact cell membrane. After a 20 per cent stretch, control myocytes remained stable and showed no fluorescence, while myocytes from mdx mice became unstable, started shaking and showed a steady increase in fluorescence, providing direct evidence for membrane damage.
In future research, U-M scientists want to test P188 on mice with other types of dystrophies and see if it works as well when given as injections, rather than infusions.
Metzger said it was uncertain whether P188 would have any clinical use in patients with muscular dystrophy. The material has been used for 24 hours to 72 hours in a phase III clinical trial for patients with sickle-cell anaemia, but questions about the safety of long-term use remain.
"If issues of dosing and long-term safety can be resolved, our research suggests that poloxamer 188 could be a new therapeutic agent for preventing or limiting progressive damage to the hearts of patients with muscular dystrophy," Metzger said.
The U-M study will be published July 17 in Nature as an advance online publication.
