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Brothers Matthew (left) and Patrick Denger attend Biddeford High School in southern Maine.

Racing time

by Tom Walsh / Photography by Francoise Gervais

It happened twice to Brian and Alice Denger.

Both of their sons—Matthew, 17, and Patrick, 15—were diagnosed with Duchenne muscular dystrophy. Matthew's diagnosis came at age five, Patrick's at almost six.

The boys are among 400 to 600 young Americans diagnosed each year with this always-fatal form of muscular dystrophy, the most common of death-sentence childhood genetic disorders. Like cystic fibrosis, Duchenne is caused by a single gene mutation. It triggers progressive muscle deterioration that usually surfaces prior to age 10. Before long, children affected—almost exclusively boys—can't walk. In time, they will require assistance with all daily activities, including eating and self-care. Eventually the inevitable cascade of muscle damage undermines their lungs and hearts. Survival beyond age 30 is wishful thinking.

I had no idea what [Duchenne] was. I do now. It's a nightmare.

In wheelchairs now, both boys attend Biddeford High School, in a community just south of Portland, Maine. A junior, Matthew will soon graduate in the top 10 percent of his class, despite not being able to walk or turn the pages of a book. Like other bright high school upperclassmen, he's now weighing his options for college.

Patrick, meanwhile, has some other priorities.

"Some years ago, I took both boys swimming," his father recalls. "Patrick was eight or nine and was still able to dress himself, but he was dawdling after our swim. I said, 'Patrick, we need to get going! What's the problem?' He said, 'I have the same thing as Matthew, right?' I said, 'Yes, you have muscular dystrophy.' He kept fumbling with his socks, and I asked him what was going on. He said, 'Am I going to need a wheelchair, like Matthew?' I said yes, that unless something happens with research, that was probably going to happen. I asked him if he was okay with that. He said, 'Oh, yeah. I just want one that is faster than Matthew's wheelchair.'"

Another New England family dealing with Duchenne is the Beckers. Amanda Becker was baffled when tests showed her infant son had a genetic disease she didn't know about, but learned of all too quickly.

"I had no idea what that was," she recalls, four years later. "I do now. It's a nightmare."

A Maine native who now lives in Massachusetts, Becker says Duchenne is "a devastating diagnosis. There's no treatment. There's nothing to slow the progression. What the Duchenne specialists can now offer my son are different versions of nothing."

The Denger and Becker families are no strangers to The Jackson Laboratory. Their advocacy on behalf of those affected by Duchenne has helped secure new federal grant funding that is expanding genetics research by Associate Professor Greg Cox, Ph.D. Cox is an expert on Duchenne muscular dystrophy, also called DMD, and other neuromuscular diseases.

"There is a genetic component to all cases of DMD," Cox says. "In about 70 percent of cases, it involves a deletion of the gene that makes the protein dystrophin. The other cases involve different kinds of mutations. Dystrophin is a protein that plays an important structural role inside muscle cell membranes. This protein reinforces the cell, like studs inside a wall strengthen that wall. Muscle cells do a lot of work, and, without dystrophin, the cellular membrane is more susceptible to damage and quickly reaches a point where it can't repair that damage."

Cox says researchers around the world are pursuing different strategies in searching for a cure for DMD. "In the sense of personalized medicine, it's a good thing that there is a multi-pronged attempt to go at it," he says. "Not all therapeutics are going to work in all patients, and it may be combinations of different therapies that prove the most beneficial. What we'd like to do here is have as many good mouse models available for the pre-clinical proof-of-principle testing before moving on to patients. We need more mouse models that have severe progression so that you can study the effects of that progression and test strategies that may impact that progression.

Associate Professor Greg Cox and Research Assistant Kimberly Huebsch discuss research results in the Cox lab.

Cox is working closely with Cathy Lutz, Ph.D., associate director of the Laboratory's Genetic Resource Science Repository. Together, they are expanding that repository's collection to include more diverse laboratory mouse models for studying the biomolecular complexities of DMD.

"We have the MDX mouse now, which has really been a workhorse as the model that is used the most to study muscular dystrophy, but we need more," Lutz says. The MDX mouse harbors a mutation in the same gene as people with muscular dystrophy, but the mice don't get as sick. "There is never just one model that shows you all you need to know, so we're trying to get some of the newer models imported into the Laboratory. We also want to develop some new mouse models that will contribute to proof-of-principle testing. We also want to improve on the MDX model and look at how different genetic backgrounds can influence the severity of the disease."

Lutz says the ever-growing inventory of DMD mouse models would be housed within a new mouse room expansion expected to come online in March 2011. "The repository is pretty much out of space at this point," Lutz says. "We're at full capacity now. To keep importing these mouse models and to make them available to researchers will require more space."

Cox and his research team are also collaborating with the Children's National Medical Center in Washington, D.C. "They do a lot of muscular dystrophy research on the therapeutic side, dealing with patients. They do a lot of pre-clinical studies as well, and we will be providing them with the mouse models they need. They want to do some compound testing in these pre-clinical trials so that we can see how efficacious these compounds are."

Much of the Laboratory's involvement in DMD research is being funded through a three-year grant of $1.44 million from the U.S. Department of Defense. "If we use this money wisely to establish the repository and to develop unique models that meet the needs of the research community, we can make some real progress," Cox says. "It's seed money. It's a starting point for using the repository to support future research."

What the Duchenne spcialists can now offer my son are different versions of nothing.

Importing and improving mouse models for a disease is a time-consuming and expensive process. The grant money is vital for improving the ability of researchers to develop better clinical therapies for DMD patients.

"I think The Jackson Laboratory, by taking on a leading role in the development of newer animal models for muscular dystrophy, will have significant impact on drug discovery," says Kanneboyina Nagaraju, D.V.M., Ph.D., of the Children's National Medical Center. "Preclinical testing in mouse models, for both efficacy and toxicity, is a critical step in translational medicine, moving promising therapies from the bench to patient bedside. The Jackson Laboratory is the best place to do this research.

"The current DoD grant is funding a collaborative effort between Dr. Greg Cox's group at The Jackson Laboratory and two groups at Children's National Medical Center led by Eric Hoffman and me. This is timely because it addresses the increasing need for better mouse models and testing of new drugs for muscular dystrophies."

Cox credits Brian and Alice Denger and their two sons for being instrumental in winning the DMD grant. Through their involvement with Parent Project Muscular Dystrophy, a national advocacy group, the family has traveled to Washington, D.C., and beyond to encourage federal support for DMD research. Sen. Susan Collins of Maine has become something of a family friend, Brian says. Maine's Second District congressman, Rep. Mike Michaud, also met the Dengers in Washington. Michaud sponsored the research request recently awarded to the Laboratory and became a high-profile advocate for securing additional federal funding for research on DMD.

"There's one thing we've learned," Brian Denger says. "Despite being such a devastating diagnosis, there is still an opportunity within families to remain cohesive. You have to choose your silver linings where you can find them, and our boys' abilities to cope and to be kids are remarkable."

Alice Denger agrees. "As devastating as it is to deal with this every day—and the boys have to deal with this more than we do—you still have to live your life. Life doesn't stop. You can't stop living because you're waiting for a cure."