Studies Point Way to New Therapeutic Prospects for Muscular Dystrophy

Abstract

AL T H O U G H 20 Y E A R S H A V E elapsed since scientists identified the protein encoded by the defective gene that causes Duchenne muscular dystrophy (DMD), treatment options to help slow the disease’s progressive muscle degeneration have remained limited. In recent years, however, therapeutic prospects have become brighter. Scientists focusing on the disease have developed some promising potential treatments, some of which are in clinical trials. In addition, a few researchers from outside the field have made some fortuitous discoveries about muscle maintenance and regeneration that are providing insights that may one day lead to new treatments. DMD is the most prevalent type of muscular dystrophy, affecting about 1 of every 3500 boys, according to the National Human Genome Research Institute. The accepted treatment is prednisone, but the adverse effects of the drug, such as weight gain, behavioral changes, bone fractures, and cataracts, almost outweigh its benefits for the boys and young men with the disease, explained Sharon Hesterlee, PhD, vice president of translational research at the Muscular Dystrophy Association. (Girls are rarely affected but may carry the mutated gene responsible for DMD, which is on the X chromosome.) “Steroids keep the boys walking longer,” Hesterlee said. “They still get weaker, but the drug slows the progression of the disease.” Scientists are looking for an intervention that halts disease progression or even reverses it, she said. Approaches targeting the disease’s genetic underpinnings are currently being explored. Patients with DMD do not produce sufficient amounts of dystrophin, a protein that is essential for proper muscle maintenance and regeneration. The gene that instructs the cells to produce dystrophin is a very long molecule that is particularly vulnerable to alterations. About 10% to 15% of DMD cases involve a nonsense mutation that prematurely stops translation of the dystrophin gene. But a team of scientists from the University of Pennsylvania School of Medicine in Philadelphia, the University of Massachusetts Medical School in Worcester, and PTC Therapeutics, Inc, in South Plainfield, NJ, have developed a drug that allows the ribosome to read through these genetic errors and produce dystrophin, yet still obey normal signals to stop translation. Recent tests of the drug, PTC124, in mice with a DMD-like disorder have shown it can lead to the production of enough dystrophin to restore muscle function (Welch EM et al. Nature. 2007;447[7140]:87-91). H. Lee Sweeney, PhD, professor and chair of the department of physiology at the University of Pennsylvania School of Medicine, explained that the advantage of PTC124 over stem cell–based therapies or other gene therapy approaches is that it is a small molecule that could easily be delivered to muscles throughout the body. Additionally, there is a large margin between the dose of the drug necessary to restore muscle function and the amount that would be toxic, so delivering a dose that is both safe and effective should be feasible. Previously, the researchers had considered the therapeutic potential of gentamicin, which has a similar effect but is much more toxic.