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Interviewee: Dean Burkin, University of Nevada, Reno School of Medicine
"On the Cusp"
"The mutation causes muscle fibers to pull away from each other and with progressive use of your muscles in these patients it eventually leads to muscle damage, severe muscle damage," explains Dean Burkin, assistant professor of pharmacology at the University of Nevada, Reno School of Medicine.
Gene therapy to replace the faulty dystrophin gene might be a solution, but Burkin and his colleagues are excited about a simpler and potentially safer approach based on work they are publishing in this week’s Proceedings of the National Academy of Sciences.
"This could be an IV drug for the patients if the work in the mouse models that we’ve been using translates to human studies," Burkin says. "That would allow a fair ease of treatment for the patients…. We’ve obviously got to do some safety tests and there’s still a few studies that we need to do. But in the field there are a number of drugs including ours that are being developed.
"These patients, especially, have been waiting a long time for new therapies to come about and I think we’re at the cusp now."
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Burkin explains that the dystrophin protein that’s absent in the muscles of patients with Duchenne acts like a glue to hold muscle fibers together. He and his team were studying a second muscle-glue-like molecule called integrin. "We had shown previously that when you upregulate, or increase, the amount of this integrin, you could alleviate muscle disease in a mouse model for muscular dystrophy," he says. "So in the last few years, we’ve been searching for compounds or molecules that would increase the levels of this integrin protein in muscle. This has led us to the discovery of this protein called laminin-111, which — when we add it to either muscle cells that are grown on a cell culture dish or whether we inject it into the mouse model of muscular dystrophy — led to an increase in this second glue-like molecule."
According to Burkin, laminin-111 is naturally present around muscle cells but only before birth. The researchers tested it in muscle cell samples from human Duchenne MD patients, and in mice with the disease.
They injected laminin-111 into one leg of the mice, called mdx mice, while injecting a placebo into the other leg as a control. They observed some of the mice as the disease progressed, and also exercised some of the mice on a treadmill, which ordinarily speeds up the progression. They found increased muscle damage in the untreated mice, but not in the treated animals.
"And so this was a significant finding suggesting that laminin-111 was really acting protective in the muscle to prevent it from degeneration," Burkin says.
The researchers also tracked the protein and were surprised to find that despite its large size, injected laminin-111 was picked up by the bloodstream and reached all major muscle groups in the mice, "including the heart and the diaphragm, which are most severely affected in Duchenne patients." This is what Burkin called "the big shocker of the study." That’s really good news because, he says, "These patients succumb eventually to heart failure or breathing difficulties…. So that was a really exciting finding and actually almost unbelievable when we saw that result."
"We don’t know exactly the mechanism of why," he says. "But immunoglobin– antibody molecules—for example, are very large and they obviously make it throughout our entire body… so maybe in hindsight it’s not so surprising."
Systemic delivery has also been a challenge for gene therapy and other approaches. While gene therapy researchers are now working with viruses with much lower cancer-causing risks, any virus— or manmade molecule for that matter— might trigger an immune system reaction.
"Laminin-111 is a naturally occurring protein and so it wouldn’t be recognized as foreign and we could inject it multiple times, theoretically… and hopefully not elicit an immune response," Burkin says.
In addition, laminin-111 could potentially benefit any patient with Duchenne, which is not only the most common type of muscular dystrophy, but also the most common lethal genetic disease among children. By comparison, the most promising drug in the pipeline for DMD patients is probably
PTC124, which is aimed at a type of mutation that only accounts for 10 to 15 percent of cases. "Theoretically, laminin-111 protein therapy should be able to treat all patients with Duchenne muscular dystrophy," Burkin says.
Of course, there are still some big "ifs." Since the mice in this study were treated before they began to show symptoms, the next step is to find out if the therapy can halt disease progression after it starts. "Most of the patients who are diagnosed with Duchenne MD, they’re diagnosed at periods between three and five years of age, and muscular dystrophy has already begun," Burkin says.
The University of Nevada has licensed its patent for laminin-111 to a Boston biotech startup called Prothelia, which is making arrangements to produce a human version of the protein for safety testing and possible clinical trials.
The small company’s founder, Brad Hodges, was a fellow researcher with Burkin at the University of Illinois early in both their careers. Hodges worked at a large biotech company from 2000 until 2007 until he decided that "working at a big company was too safe." He wanted to develop therapies for muscular dystrophy patients. "Large companies typically don’t develop drugs," Hodges says. "They typically buy them from small companies that take the early-stage risks.
"I set myself a goal," he says. "I’m going to get at least one drug approved for muscular dystrophy. I’m going to do it; it needs to be done. Patients deserve it and there’s a critical need." Hodges cashed in his 401k and began "living on the edge."
As he looked around for candidates, he kept abreast of Burkin’s research, and laminin-111 is now the first product in the company’s "pipeline." Hodges credits the Parent Project Muscular Dystrophy, or PPMD, for supporting him as he wrote grant proposals under NIH’s Small Business Innovation Research awards program. "I wake up every morning so excited—and a little bit frightened at the same time," Hodges says.
In addition to Burkin’s latest results, Hodges recently received the good news that Prothelia will receive $250 thousand from NIH in June that will support its efforts for six months. He says it will take twice that just to get safety studies started.
But most importantly, he says, "I will have to demonstrate to myself, as well as to everyone else, that this drug is for real."
This research was published in the Proceedings of the National Academy of Sciences early online edition the week of April 20 – 24, 2009; American Journal of Pathology, January 2009, and was funded by the National Institutes of Health (NIAMS & NINDS).
Elsewhere on the Web:
Muscular Dystrophy Association: "Helping Jerry’s Kids"
Limb-Girdle Muscular Dystrophy Gene Therapy First to Show Promise Beyond Safety
Update on Clinical Trial of Lab-Engineered molecule for Duchenne treatment