For years, scientists have been devising ways to treat Duchenne muscular dystrophy - the most common and serious form of the disease - without actually replacing the mutated gene that causes it. That approach may soon pay off, as researchers start testing the most promising of such techniques.
H. Lee Sweeney, a researcher and professor at Penn's School of Medicine is among a "probable majority" of researchers who have shifted their focus from gene therapy to treatments that override the effects of specific mutations.
Duchenne victims, nearly all male children, have a mutated version of the gene for the muscle protein dystrophin, usually a version that lacks "coding" regions, where instructions for protein production are contained. As a result, they can't repair muscle damage from everyday exertions like climbing stairs.
Sweeney noted that "the real mindshift among scientists probably took place around a decade ago . it's just now that they're actually trying these out on patients."
Several prominent mutation-specific treatments are currently in or nearing clinical trials.
In connection with the pharmaceutical company PTC Therapeutics, Sweeney has been developing a drug that will induce ribosomes to continue producing dystrophin even when a gene with a "nonsense" mutation tells them to stop prematurely.
Based on mouse trials, Sweeney speculated that the drug could halt the disease in young victims of the mutation -- 15 percent of Duchenne patients -- and stabilize it in older ones. But even then, they would only be able to lead a "relatively sedentary life; they wouldn't be able to go out and run very much," he said.
Dutch researcher Judith van Deutekom said her team is developing a drug that aims to "delay or even stop progression of the disease, but hopefully also improve muscle function" by creating a smaller but functional gene out of the 70 percent of Duchenne genes that lack coding regions.
After the 1986 discovery of the gene responsible for Duchenne, researchers first tried to use gene therapy - replacing the defective coding regions of the gene with healthy ones - but had trouble effectively inserting those replacements into muscle tissue.
"You'd never wipe out this disease with genetics alone, because you have a high new mutation rate," said Tejvir Khurana, a researcher at Penn's Mahoney Institute of Neurological Sciences.
"Gene therapy is still essential given the fact that some mutations are just not curable otherwise," Van Deutekom said. But a workable gene therapy may be far off.
"I still think those problems [of insertion] will take decades to figure out," Sweeeney said.
Despite new approaches, ensuring that Duchenne patients don't have respiratory failure as their lung muscles degenerate is still "the single most useful thing you can do," Khurana said.
He added that Duchenne treatment has made great strides even without a gene therapy cure.
"Typically most clinicians have Duchenne patients now who are in their forties or late thirties," he said. "Even 10 or 15 years ago, it would be unheard of to have a patient live up to 20."
*The following correction ran in the March 18th issue of the DP:
In Friday's article on muscular dystrophy research ("MD researchers muscle in on more targeted treatments," DP, 03/7/08), we incorrectly affiliated Tejvir Khurana with Penn's Mahoney Institute of Neurological Sciences. He is primarily affiliated with the Department of Physiology and Pennsylvania Muscle Institute.
