A strong muscular dystrophy research team responds to an urgent need for new therapies
Every week, University of Minnesota neurologist John Day, M.D., Ph.D., sees muscular dystrophy patients in the clinic, and every week, he says he gets a “kick in the rear.”
Day conducts research aimed at understanding and eventually curing muscular dystrophy. But as he sees his patients’ disease progress weekly, he is reminded that research can’t move fast enough. “When you’re working in the lab, it’s very easy to be impressed by and enamored with the progress that’s being made,” Day says. “It’s really exciting. It feels like it’s happening at breakneck speed. But then you go to the clinic and realize it’s not nearly fast enough. People are living with and dying of this disease today.”
One particularly devastating form is Duchenne muscular dystrophy, which affects young boys. Parents will usually notice by the time their son is 3 or 4 years old that he just isn’t keeping up with other kids his age.
The boys, whose muscles get progressively weaker, will likely be in a wheelchair by their early teens. Most will die in their 20s.
“Treatment for this disease is woefully inadequate at the moment,” says Day, who directs the University’s Paul and Sheila Wellstone Muscular Dystrophy Center. “The only thing that has had any effect is corticosteroids, and there is a whole host of side effects with those drugs.”
For many families affected by muscular dystrophy, the University offers a beacon of hope. A large group of researchers here continues to make scientific advances in Duchenne and myotonic dystrophies, as well as other forms of the disease, while a new-to-the- University group of investigators adds power to their efforts.
“What distinguishes this place in part is this breadth of scope on these diseases,” Day says.
Today the Paul and Sheila Wellstone Muscular Dystrophy Center helps to coordinate the efforts of 30-some faculty members from 14 departments and four schools across the University, including the Medical School, College of Veterinary Medicine, Institute of Technology, and College of Biological Sciences. These faculty collaborate with other scientists and clinicians around the world to bring the most promising treatments to patients as fast as possible.
“There’s just an enormous momentum right now,” says Michael Kyba, Ph.D., a
stem cell scientist and facioscapulohumeral dystrophy (FSHD) researcher who moved his lab to the University in 2008.
Searching for answers
Duchenne muscular dystrophy is caused by a genetic mutation preventing the body’s production of dystrophin, a protein crucial to maintaining muscle structure. The disease is generally characterized by progressive deterioration of the muscles in the body that control all movement, including those needed to move the arms and legs and also to speak, swallow, and breathe.
Different forms of muscular dystrophy vary in terms of how much muscle weakness they cause, which muscles they affect, how quickly the diseases progress, when symptoms appear, and how they’re passed from generation to generation.
All muscular dystrophies, however, have this in common: There’s no known cure and no proven way to stop their progression.
But one University research team, led by biochemist James Ervasti, Ph.D., recently obtained promising results in the search for a treatment for Duchenne.
The team injected a mouse model with a substitute for the missing dystrophin, repairing the weakening muscle tissue. The substitute is a modified protein called utrophin—a dystrophin relative—with a cell-penetrating tag known as TAT. The team found that, once injected, TAT-utrophin efficiently spreads throughout the body.
This approach overcomes major hurdles in treating Duchenne because it delivers the therapy to every muscle cell in the body. Also, because every cell makes utrophin naturally, the immune system does not reject the therapy.
It’s not a cure, but Ervasti says this treatment could one day be an effective therapy for boys with Duchenne, very much like lifesaving insulin shots for people who have type 1 diabetes. And the work keeps advancing.
“We have made substantial progress in optimizing the TAT-utrophin for future clinical trials in humans, which we hope will commence within three years,” he says.
A discovery with help from a Minnesota family
The University is one of two major research hubs nationally focused on mytonic dystrophy, the most common form of muscular dystrophy in adults, Day says. (The other major center is the University of Rochester in New York, with which the University team frequently collaborates.)
Myotonic dystrophy often goes undiagnosed because it not only causes muscle weakness but also can cause diabetes, cardiac arrhythmias, early cataracts, and infertility, among other health problems.
“[Physicians] don’t know how to think about it,” Day says. “It’s listed as a muscular dystrophy and it is a muscular dystrophy, but it affects every other organ system as well, often leading to confusion about which clinical problem is the primary underlying cause.”
The University team’s renown in this area stems from its 2001 discovery of the gene that causes myotonic dystrophy type 2. This breakthrough study, led by Wellstone Center research director Laura Ranum, Ph.D., and Day, involved 60 members of a northern Minnesota family known to carry the disease.
The gene mutation that causes myotonic dystrophy type 1 had been discovered nearly 10 years earlier by scientists in England and Texas, but researchers still weren’t sure how that mutation caused disease. The discovery of the second genetic form showed that both types of myotonic dystrophy were caused by abnormal RNA, the messenger molecule that translates DNA code into proteins.
“[The discovery] allowed us finally to understand the mechanism of myotonic dystrophy types 1 and 2,” says Day, and nail down a target for future therapies.
Today Ranum and Day—along with colleagues Timothy Ebner, M.D., Ph.D., and H. Brent Clark, M.D., Ph.D.—are completing the second year of a five-year National Institutes of Health (NIH) study in collaboration with the University of Florida aimed at learning more about brain changes in people who have myotonic dystrophy. The disease can cause both developmental and degenerative brain function, producing mental retardation in some children and dementia in some adults.
“It’s the thing that most affects patients,” Ranum says. “There are marked effects on cognitive function and patients’ ability to plan and carry out their everyday tasks.”
Through the NIH grant, Ranum’s group is creating a mouse model of myotonic dystrophy and will examine whether brain changes that occur in the mice also occur in humans.
It’s a great example that shows how neurodegenerative diseases are related, Days says, and that a breakthrough in one disease area could lend knowledge about other diseases as well.
“You think of muscular dystrophy as being completely on the other end of the spectrum from Alzheimer’s disease, but that’s just not true,” Day says. “People with muscular dystrophies very commonly have central nervous system abnormalities directly due to their disease.”
Heart repair with a Band-Aid
Muscular dystrophy often affects the brain and all muscles, including one of the body’s most important muscles — the heart. Duchenne muscular dystrophy, for example, causes muscle degeneration in the heart and progressive cardiomyopathy, Day says. Eventually, the heart can just stop pumping.
That’s why Joseph Metzger, Ph.D., chair of the Medical School’s Department of Integrative Biology and Physiology, is developing a new therapy that
He calls it the “molecular Band-Aid.” When injected into the bloodstream, this chemical Band-Aid seeks out tiny cuts in the heart muscle and protects them from harm so that the heart can function normally.
Metzger has studied the potential of this therapy in large animals and hopes to begin clinical trials in humans soon.
“We are encouraged by the present findings,” says Metzger, who holds the Maurice Visscher Land-Grant Chair in Physiology. “We’re very much interested in applying this to Duchenne patients and more broadly to acquired diseases of the heart.”
Restoring muscle function with stem cells
Improving muscle function from a different angle—with the use of embryonic stem cells—is the research focus of Rita Perlingeiro, Ph.D. Her recent findings have significant implications for advancing new therapies for muscular dystrophy.
But first, she faced some hurdles. Making muscle cells from embryonic stem cells in a Petri dish wasn’t easy to do, says Perlingeiro, an associate professor who joined the Division of Cardiology in 2008. “We were seeing that muscle cells were inefficiently produced, and not enough of them were being produced to make muscle,” she says.
But using a gene called PAX3, Perlingeiro essentially “instructed” embryonic stem cells to make muscle cells instead of other cell types.
Once enough muscle cells were produced, Perlingeiro’s team injected them into the injured muscles of mice that have muscular dystrophy. Upon transplantation, the cells not only helped to grow muscle tissue but also improved muscle function.
Her lab team has shown that this approach can restore function to defective muscles in mouse models of Duchenne and FSHD.
Searching for the best treatment target
To help steer future FSHD treatmentand cure-focused research down the right path, Kyba and his team are studying how the gene variation that causes FSHD, the third most common type of muscular dystrophy, causes muscle loss.
Scientists know that FSHD is caused by a missing piece of DNA that is part of a repetitive sequence. This area of DNA normally has about 100 copies of this particular sequence, Kyba says, but people who have FSHD have 10 or fewer copies.
“So there’s something in this repeat sequence that causes the disease when you have only 10 repeats but doesn’t cause the disease when you have more than 10 repeats,” he says. “Genetically, it’s a very mysterious disease.”
Kyba wants to know why this happens. By removing cells from people who have muscular dystrophy and reprogramming them to become induced pluripotent stem (iPS) cells, the team expects to gain insight into the genetic basis for this form of muscular dystrophy and hopes to find ways to genetically repair that diseasecausing defect.
“The protein encoded by this repetitive sequence is probably the best target for therapeutic intervention in FSHD, but we really haven’t proven it yet,” Kyba says. “We hope to use the iPS cells to show that the protein is expressed in muscle stem cells and validate that idea.”
Help for patients today
While University research teams get closer and closer to finding better ways to treat the root causes of muscular dystrophies, they acknowledge that translating lab work into therapies for patients takes time and money.
And Day is reminded—every week—that his patients need help now.
For some Duchenne patients, that help comes in the form of clinical trials. The University is one of the largest centers for Duchenne muscular dystrophy trials in the country, Day says, because of its participation in a five-site clinical research network through the Muscular Dystrophy Association.
For one subset of boys with Duchenne, early clinical trials are under way using a medication to potentially slow—or even stop or reverse—the effects of the disease. The University was one of 10 sites nationwide involved in a Phase II clinical trial to test the drug’s effectiveness on boys whose Duchenne was caused by a single letter change on the dystrophin gene—about 10 to 15 percent of cases—and who can still walk.
The University is the lead site on another study testing the drug on boys with the same dystrophin mutation who have more advanced disease and can no longer walk.
And in September the University scientists hope to join a new treatment trial aimed at altering the way RNA is processed in boys who have Duchenne. This drug would essentially put an artificial patch over the abnormal section of RNA so that the boys’ muscles would produce a nearly normal dystrophin protein, only missing the piece with the genetic flaw. The mouse studies of this approach are “dramatic,” Day says.
“We are eager, obviously, to be able to treat all boys,” Day says. “Part of our whole effort here is correcting the disease and the underlying problem, but it’s also making sure that these boys and young men are living as full and active lives as they can.”
By Nicole Endres