by Margaret Wahl

Richard Moxley examines Carol Harrier, who has myotonic dystrophy and has participated in research studies at URMC.

Carol Harrier, 59, of Seneca Falls, N.Y., remembers 1992 as the year she first noticed that she was getting weaker and could no longer keep up with the physical work of running the farm she and her husband, Don, owned and operated.

Her doctor thought Harrier, then 47, might have arthritis, but her condition didn't respond to treatment for that.

A visit to a local neurologist resulted in a referral to the University of Rochester Medical Center and to Richard Moxley, now professor of neurology and pediatrics and director of the Neuromuscular Disease Center at URMC.

At URMC, Harrier not only got the right diagnosis myotonic muscular dystrophy but also received treatment for some of her symptoms and the chance to participate in research studies.

"I'm interested in feeling better," Harrier says. "But I'm also interested in helping others."

That's what clinical care and research are about at URMC, which is now, thanks to legislation passed three years ago, one of the nation's three Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers.

A 'Center of Excellence'

By 2001, URMC's research and clinical programs in neuromuscular disease already were well known. But that year brought a special opportunity.

In December, President Bush signed into law the MD-CARE Act (Muscular Dystrophy Community Assistance, Research and Education Amendments of 2001), which resulted from the efforts of MDA and other groups and of Sen. Paul D. Wellstone of Minnesota, who would die in a plane crash a year later. (The centers were later named in his honor.)

The act stipulated that the National Institutes of Health (NIH) establish "centers of excellence" to develop treatments and cures for the muscular dystrophies.

Last year, NIH and MDA formed a partnership to support the centers. NIH agreed to provide each center with a maximum of $1 million a year for five years, and MDA promised up to $500,000 a year for each facility for three years.

When the NIH announced that the centers would be established, Moxley thought Rochester stood a pretty good chance of being awarded one of the grants.

"We already had a long history of doing research involving therapeutic trials and pathophysiology and to some extent research in the molecular biology of the muscular dystrophies," he reflects.

URMC had an especially long track record, Moxley notes, dating back to its role in the Collaborative Investigation of Duchenne Dystrophy (CIDD) Group, established by MDA in 1978. This group included physicians, other health care professionals and scientists at Rochester and three other university medical centers, who studied the natural history of Duchenne muscular dystrophy and conducted tests of experimental treatments for that disease.

"We had that as a background," Moxley says, "along with a background in myotonic and FSH dystrophies."

Believing that other institutions applying for the new grants were likely to focus on Duchenne MD, Moxley and his group decided to focus their application on myotonic muscular dystrophy (MMD) and facioscapulohumeral dystrophy (FSHD).

"It's not that we're not interested in Duchenne dystrophy and other dystrophies," he notes. "We are but from an application standpoint, we felt our strongest suit at that time was in those two diseases. We had more hard data that we could quote and more active grant work, so that when people looked at our application, they could say, 'Those people are on their toes.'"

The strategy worked, and last year URMC was named as one of three Wellstone cooperative research centers. The other centers at the University of Washington in Seattle and the University of Pittsburgh focus mostly on Duchenne MD.

All three centers as well as new ones that may receive grants in the future have been asked to cooperate with each other.

"Already we've had three get-togethers, two by phone and one in person at NIH," Moxley notes. "The people running the different centers have begun to discuss how they can best interact, how they can grow to be stronger than the sum of their parts."

Solving an 'Impenetrable Mystery'

Charles Thornton, co-director of the MDA Clinic, examines muscle cells from mice with muscular dystrophy.

If you were looking for a physician who spans the gap that often exists between basic scientists and clinicians, the URMC's Charles Thornton would be a good example.

Thornton is an associate professor of neurology as well as a co-director of MDA's Neuromuscular Disease Center Clinic at URMC. He's also equally at home in the lab, studying the molecular basis of the diseases he sees in the clinic.

One of Thornton's basic science projects, and a key part of the Wellstone Center, is understanding how the apparent disabling of a group of proteins known as muscleblind may be a major factor in causing myotonic MD.

The more common type of MMD (type 1) is caused by an expanded section of DNA on chromosome 19, known as a triplet repeat. The expanded DNA results in expanded RNA, a close chemical cousin of DNA. This RNA appears to stick to muscleblind protein molecules and disable them.

Recently, it's been found that the less common type 2 MMD is caused by a similar expanded DNA section on chromosome 3.

Thornton says his group is "fairly confident that the effect of this triplet repeat RNA is to sop up the supplies of muscleblind protein so it can't work and that the same thing happens in humans as in mice."

Thornton studies projected images of nerve cells from people with myotonic dystrophy.

Thornton's research isn't restricted to the muscle effects of MMD, which is a multisystem disease. Abnormalities in MMD-affected nerve cells in the brain may lead to unusual patterns in the sleep-wake cycle and some more subtle effects, such as apathy or learning problems, experts have speculated.

So far, Thornton says, "It looks like the lessons that have been learned in studies of the muscle cells may also apply in the nerve cells."

Until recently, Thornton says, "the major focus has been on looking at how this triplet repeat RNA might cause problems inside muscle cells. There was controversy about whether that RNA even exists in brain cells, and whether it could cause any trouble there." It's now clear that it not only exists but that it likely causes the same sort of trouble, Thornton has found.

The implications go far beyond academic curiosity.

"The exciting thing about all this is that it raises a number of therapeutic possibilities," Thornton says. "For example, could we overcome the problem just by increasing muscleblind? Could we find a way to pry it loose from RNA? Could we find a way to help muscle and brain cells get rid of the RNA more rapidly? These are all exciting possibilities."

Until a few years ago, Thornton says, understanding the true effects of the genetic mutations in MMD had seemed an "almost impenetrable mystery." In the last three years, progress, he says, "has been tremendous."

Following the Sleep Pathway

Emma Ciafaloni, assistant professor of neurology, has an MDA grant to study excessive sleepiness in myotonic dystrophy.

Not far from Charles Thornton's lab is the office of Emma Ciafaloni, assistant professor of neurology and recipient of an MDA grant to study excessive sleepiness in MMD.

Ciafaloni is part of the Neuromuscular Disease Center at URMC and is affiliated with the Wellstone Center as well.

"All projects here are related in a way," she says.

Ciafaloni, originally from Italy, came to URMC in 2002 from Duke University in Durham, N.C., where she directed the MDA clinic.

"When I was at Duke, I saw a lot of myotonic dystrophy patients," Ciafaloni says. "And the observation came to me that many of these patients, even when they had pretty mild muscular problems, were very disabled.

"Most of them were out of work and spent most of their days at home, while we had patients with other muscular dystrophies who were very active and kept working. The complaint of feeling sleepy all the time came across."

Excessive daytime sleepiness has long been observed in many people with MMD, but its origins have been unclear. Some doctors have concluded that respiratory muscle weakness, resulting in interrupted nighttime sleep, is the primary cause.

Ciafaloni talks with Carol Czebatol, who has myotonic dystrophy and is participating in the sleep study.

Ciafaloni doesn't think that's the whole story.

"It turns out that many patients do not have sleep apnea [breathing interruption] from respiratory muscle weakness," she says. "Some patients even when still very strong have this pattern on a sleep study that looks similar to another disease."

That disease is narcolepsy, a neurologic disorder involving excessive sleepiness during the day and irresistible "attacks" of sleep while going about everyday activities.

The resemblance started Ciafaloni thinking.

"It points to a central nervous system problem, a brain problem," Ciafaloni says. "And we know that myotonic dystrophy affects many systems, not just muscles."

Participants in Ciafaloni's study undergo an overnight sleep study (polysomnogram), which measures brain waves, muscle activity and heart function; and a multiple sleep latency test, which measures how quickly they fall asleep at intervals during the next day.

They also undergo a lumbar puncture to get a sample of the fluid surrounding the spinal cord. That procedure enables Ciafaloni to measure the nervous system protein orexin, which is diminished in narcolepsy and is believed to help regulate the sleep-wake cycle.

Sleep and the orexin pathway, as Ciafaloni describes it, might in fact be a window to the nervous system abnormalities in MMD.

"It's an easier thing to study than other central nervous system things, and it may give us a clue about the CNS phenotype [symptoms]," she notes.

Meanwhile, nearby, Thornton's study of brain cells from people with MMD will include looking to see if there are abnormalities in orexin or related molecules.

"The goals cover several clinical questions," Ciafaloni says of this study, "but they also cover the molecular biology and the basic pathophysiology of this disease."

Building Muscle With Biotechnology

Richard Moxley, Neuromuscular Disease Center director, confers with Christine Quinn, who coordinates clinical trials.

The dream of finding a compound, or drug treatment, that could circumvent, if not correct, the underlying defect in muscular dystrophy has been around for a long time and Richard Moxley has shared it.

Beginning in the 1980s, Moxley and his colleagues at URMC began testing in patients with myotonic MD various compounds they thought would have muscle-building (anabolic) effects. They tried the male hormone testosterone; human growth hormone; and troglitazone, a drug that enhances the body's response to insulin, a hormone that helps build muscle. (Insulin resistance is common in MMD.)

Some of the drugs increased the manufacture of needed proteins in muscle tissue. And troglitazone (since taken off the market because of concerns about its effects on the liver) improved the sensitivity of the cells to insulin. But the hoped-for changes in strength didn't follow.

Then, in 1995, a group at what was then New York Hospital-Cornell Medical Center announced they'd seen some interesting effects with insulin-like growth factor 1 (IGF1) in people with MMD.

The trial of this compound was small, and several people had significant side effects, but those who stayed in the study and got the highest doses of IGF1 showed some benefit. Some even showed functional improvement, such as better stair climbing. They also responded better to insulin and made more muscle protein.

Moxley wanted to pursue the findings, but the company supplying the drug lost interest.

A few years ago, Moxley heard from a small biotech company called Insmed, of Glen Allen, Va.

"They said, 'We were talking with some people who said you were interested in looking at IGF1 in myotonic dystrophy.' I said, 'You're absolutely right.' Then they told me about a combination protein that they had."

The combination was one of IGF1 and IGF binding protein 3. The resulting compound mimics the state in which IGF1 normally travels through the body, seemingly minimizing side effects, boosting safety and perhaps allowing high enough doses of IGF1 to be given.

Insmed told Moxley it had studied this anabolic compound in healthy women, in elderly women with hip fractures, and in people with burns, with encouraging results.

"The fact that they were able to give this compound to these patients who were fairly sick made me think: If those people can tolerate it, I'm pretty sure our healthier patients with myotonic dystrophy can tolerate it, without significant side effects," Moxley recalls. (IGF1 alone can cause acute lowering of blood sugar.)

Insmed teamed up with Moxley to test its new IGF1-IGFBP3 combination, now called SomatoKine, in patients with MMD. The trial is slated to begin later this year.

"Its an excellent example of the teamwork that MDA is participating in, joining with NIH and with other groups," Moxley notes. "In fact, this is a very specific example of how MDA has helped bring together NIH efforts, MDA efforts and also a private company."

A New Look at FSHD

Rabi Tawil, associate professor of neurology, talks with Julianne Viviani, who has facioscapulohumeral dystrophy.

Rabi Tawil, associate professor of neurology, director of the Muscle and Nerve Pathology Lab, and co-director of the MDA clinic at URMC, wants to take a closer look at people with FSH muscular dystrophy.

"One of the interesting things that a lot of patients report is that things seem to be stable for a long time, and then suddenly they develop pain and lose function in one muscle," he says.

Then there's the asymmetrical weakness and wasting in FSHD, which isn't typical of most other dystrophies.

"You can have one normal biceps and the other can be completely wasted," Tawil says. He asked himself, "Could this be the equivalent of some trigger activating an ischemic [related to loss of blood flow] process?"

Tawil and colleagues have shown that genes controlling the activity of smooth muscle cells, such as those that line the blood vessels, are highly active (what scientists call upregulated) in people with FSHD.

He suggests that some of the known vascular, or blood-vessel-related, abnormalities in FSHD, such as retinal problems, might be a more important clue to muscle wasting than previously believed.

"There seems to be a connection between the two, and we're trying to investigate that further," he says.

Tawil is collecting muscle samples to look more closely at differences in gene activity between people with FSHD and those without the disease. He's also examining the structure and number of blood vessels in FSHD-affected muscle tissue.

"The reason we're able to do a large study is that we have all these resources here," Tawil says.

An Integrated Approach

"The center is about taking an integrated approach to finding treatments," Charles Thornton says of Rocheste'rs Wellstone Center.

"It's a place where there's a group of scientists that works closely together, at the same time, trying to understand exactly what's making muscles become weak in the laboratory and in our patients and quickly translate this into testing new treatments.

"We learn from the patients participating in treatment testing about what's causing muscles to become weak, and then that often goes on to [other] treatment testing."

Basic science and clinical research "push each other forward," Thornton says. "There's a synergy in doing both things at the same time. The threads reinforce each other."