A Race Against the Clock: Parents, Researchers Lobby for Accelerated Duchenne Muscular Dystrophy Research

Marissa Penrod knew something was wrong with her son early on.

At the age of four, Joseph was unable to run. He couldn't normally walk up a flight of stairs, having to take each step two feet at a time. He has never ridden a bike.

After multiple consultations with a pediatrician, the Penrods were referred to a neurologist in Ann Arbor, Mich., where Joseph underwent blood and laboratory tests focusing on creatine kinase, a liver enzyme that regenerates muscle tissue in the body.

Normal CK levels average around 300. Joseph's levels clocked in at more than 20,000 -- akin to levels found in marathon runners -- an indication of extreme muscle breakdown.

Genetic tests later confirmed the diagnosis of Duchenne muscular dystrophy, a deadly childhood disease that few survive past their early 20s.

Instead of becoming overwhelmed with grief, Penrod took a proactive approach with her son's diagnosis. After research and conversations with experts, in 2009 she founded Team Joseph, a nonprofit organization aiming to fundraise for research and bring more exposure to Duchenne.

"I let myself have a really big pity party for about a day. And then I decided that really wasn't going to help Joseph," Penrod said. "This is sort of a really profound example of you can't always choose what you've been handed, but you can always choose how you handle it."

This year, Team Joseph is the primary beneficiary of Northwestern University's Dance Marathon, a 30-hour event that's been raising money for charities since 1975. The organization stands to gain much from DM, an increasingly popular on-campus event that has raised more than $1 million the past two years.

The money generated from DM comes at an important time for research on Duchenne prevention and treatment alternatives, which have made notable progress in the past two decades but are in need of additional funding for research and clinical trials. Team Joseph and other Duchenne organizations are working with the Food and Drug Administration and members of Congress to try to accelerate research for the disease, but it is a slow process -- too slow for a disease with such rapid progression, Duchenne advocacy groups argue.

There is still no approved cure or treatment to halt or slow the progression of Duchenne. But advances in drug therapy and genetic research since the mid-1980s have generated hope for those fighting the disease today.

A meaningful journey

Duchenne muscular dystrophy is a debilitating genetic condition that causes muscle fibers to deteriorate rapidly, leading to an extreme loss of muscle mass. It results from a error in the dystrophin gene, which provides coding for a protein that determines the structure of muscle tissues.

With visible symptoms manifesting before the age of 6, most Duchenne patients lose the ability to walk by 11 -- Joseph's current age. Motor skills and skeletal and muscle formation deteriorate over time, and by 21 many are essentially paralyzed from the neck down. The majority die from either heart attacks or respiratory failure.

"Duchenne's worse than cancer," said Eric Hoffman, a longtime Duchenne researcher and director of the Research Center for Genetic Medicine at George Washington University. "With Duchenne you just relentlessly fade away over 20 years. As a parent, to watch that with your child is just devastating."

The most common form of childhood muscular dystrophy, Duchenne affects about 1 in 3,500 young boys, the primary demographic impacted by the disease. About 20,000 new cases of Duchenne are diagnosed annually.

Everyday life is not easy for Joseph. He cannot participate in team sports, sometimes struggles to keep up with his friends and has to be carried up flights of stairs. But Joseph is lucky in that he can still walk and function on his own to an extent, and his experience coping with the disease can serve a greater purpose, his mother said.

Despite Duchenne's bleak nature, Penrod has maintained a proactive outlook in seeking cures and treatments for her son and other boys diagnosed with the disease through Team Joseph.

"I wanted to make sure that Joseph's life and his journey -- whatever it would entail -- that it would have some kind of meaning and that we would use it for something really good," Penrod said. "That made me want to do everything we could to find a treatment."

Searching for a cure

Duchenne patients face a sparse treatment landscape.

Duchenne is treated primarily with steroids and artificial ventilation machines, both of which have serious drawbacks. Steroids stunt patients' growth and make bones so brittle that children lose the ability to walk two to four years earlier than they would have without them. Ventilation machines also detract from quality of life and make patients completely reliant on caregivers, Hoffman said.

But although no FDA-approved cure or treatment for Duchenne currently exists, today researchers and drug developers now know enough about the disease's origins to be working on treatments to halt and potentially reverse its progression.

Potential treatments fall under four categories: Exon-skipping drugs that trick cells into ignoring mutations in the dystrophin gene, muscle stem cells, direct gene therapy and drugs that slow down muscle inflammation and regenerate tissue, said Jeff Chamberlain, a neurologist at the University of Washington working on several muscular dystrophy projects.

"We're at the point now where things can be done," Chamberlain said. "And 20 years ago there weren't things that could be done."

Researchers are also looking at the possibility of using hormone-based drugs like Relaxin, which has been used to improve blood flow in pregnant women. In initial studies, the drug increased blood flow to muscles and could possibly reverse muscle damage in Duchenne patients, said Ron Berenson, a researcher working with Chamberlain at UW's Center for Commercialization.

Ultimately, the definitive cure for Duchenne will be gene therapy that replaces the defective dystrophin gene, but experts say it will be years before that option is available.

"These things take time and I think it will take a few decades before that happens," Berenson said. "I wish it would go faster, too."

Struggling to accelerate research

Despite positive advances in research, experts and advocacy groups differ on the best approach to tackling Duchenne and whether the FDA and Congress are truly making the disease a priority.

Eteplirsen, an Exon-skipping drug, has been a sticking point between Duchenne advocacy groups and FDA representatives, who have yet to place the drug on a track for accelerated approval. The lack of progress on the issue has been source of frustration for parents, legislators and Duchenne nonprofits, including Team Joseph.

Although experts say the drug shows promise, it treats only a small subset -- 13 percent -- of Duchenne cases, as it's tailored to specific gene mutations.

Publicly, the FDA has not shared its conclusions on accelerated approval for Eteplirsen, citing their "evolving position" on the drug and the ongoing analysis of Duchenne treatments "based on thorough and extensive assessments and discussion of all available data and information by a large multi-disciplinary team of FDA scientists."

"We recognize the huge unmet medical need in Duchenne muscular dystrophy, the devastating nature of the disease for patients and their families, and the great urgency to make new treatments available," the FDA wrote in a statement.

Multiple scientific experts on Duchenne say drugs like Eteplirsen are encouraging and have yielded compelling results. However, a few researchers disagree over whether the data supports granting accelerated approval for the drug. Sound clinical trials need to be double-blinded to combat the placebo effect, Hoffman said, and the drug will not broadly cure Duchenne.

"Parents are desperately looking for anything that can improve the quality of life of Duchenne kids. Everybody's desperate," said Hoffman, who is working on alternative Duchenne therapies. "To think that the regulators are somehow purposely keeping a drug from patients couldn't be further from the truth."

Others, however, are not as optimistic about the FDA's approach. Berenson called the agency "extremely difficult" to work with and unwilling to modify a mindset focused on safety, one that does not readily apply to rare, urgent diseases like Duchenne.

Multiple other Duchenne experts met with the FDA last month to discuss the evidence supporting Eteplirsen.

At a briefing in early February that was attended by staffers from more than 80 congressional offices, several leading Duchenne experts touted Eteplirsen's promising results and emphasized the lack of negative side effects.

"This drug works," Jerry Mendell, the drug's lead investigator, said at the briefing. "It has minimal side effects. I say minimal -- we haven't seen a single one, which is incredibly remarkable."

Louis Kunkel, a Harvard Medical School professor and discoverer of Duchenne's link to the dystrophin gene, also praised the new therapy.

"They are stabilized," Kunkel said of the boys who have received the drug. "They are making dystrophin. This is really quite an amazing feat."

Parents who feel time is running out for their children may be more amenable to taking risks with treatment, said Pat Furlong, president of Parent Project Muscular Dystrophy. The group is currently expanding a survey in which parents of children with Duchenne said they would be willing to participate in risky therapies due to Duchenne's serious nature.

A report based on the survey recommended the FDA grant accelerated approval for Duchenne therapies, improve flexibility in its approval processes for deadly disease treatments and "amplify the patient voice in drug evaluations."

The rare and severe nature of Duchenne makes additional clinical trials especially problematic, Penrod said. Placebo trials would prevent some boys from receiving drugs and involve muscle biopsies under general anesthesia -- especially dangerous for those with Duchenne. The requirements are unnecessary, Penrod says.

Even though the drug would not treat Joseph's strain of Duchenne, Penrod supports efforts for its accelerated approval.

"I know this and I believe it without a doubt: We will find a treatment for Duchenne," Penrod said. "I don't think we're on a race against the science. It's like we're on a race against the clock. It's how quickly we do it."

A group effort

As is the case with many diseases, research for Duchenne requires an enormous amount of time, energy and money.

Team Joseph, PPMD and other Duchenne organizations are working together and with legislators to accelerate research and boost funding, in part by seeking reauthorization of the 2001 Muscular Dystrophy Community Assistance, Research, and Education Act.

The bill, which expires every five years, requires the National Institutes of Health to prioritize muscular dystrophy, establishing programs and funneling funds into research. The bill has generated nearly $500 million worth of research and programs benefiting muscular dystrophy, Furlong said.

"That legislation has touched in one way or another every single scientific strategy and every single trial that we see today," Furlong said.

Up for reauthorization this year, 78 members of Congress currently support renewing the MD-CARE Act. Additionally, Team Joseph and other groups are working with the FDA to accelerate Duchenne research under provisions of the 2012 Food and Drug Administration Safety and Innovation Act, which created new approval routes for drugs treating rare and deadly diseases.

Last July, Rep. Spencer Bachus (R-Ala.), a co-sponsor of the MD-CARE Act, testified before the House, advocating for the approval of Eteplirsen and increased Duchenne research. Bachus has also signed letters urging the FDA to expedite access to Duchenne treatments like Eteplirsen.

"I am concerned that the FDA has not adequately taken into account the views of the Duchenne community and the unmet need of medication to treat Duchenne," Bachus wrote to Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, in December. "The families and even young Duchenne patients tell me that, due to the debilitating nature of Duchenne, they are desperate for a solution and willing to assume all risks because time is unfortunately not on their side."

Despite its critics, the FDA has solicited feedback from the Duchenne community. In December, it held a policy forum with Duchenne stakeholders, where Penrod testified against delaying potential treatments to sick children. FDA officials said they recognize the "dire urgency of the situation."

"We will continue to work relentlessly with the community to make safe and effective treatments for Duchenne muscular dystrophy available to patients," the FDA said in a statement.

A 'transformational' experience

On Friday, March 7, more than 1,500 Northwestern students will gather in a large white tent behind the university's student center. Kicking off at 7 p.m., the students will dance for 30 hours straight into the early hours of Sunday morning just days before final exams.

Despite continuing struggles with the FDA, Penrod said she is proud of Team Joseph's accomplishments and of the way her son has coped with and adapted to the disease.

The money raised through DM will be a game-changer for Team Joseph and her son, Penrod said.

"We've been really grassroots and really event driven. We've had some amazing individual donors who've helped along the way. But it's primarily through individual giving and events.

"Dance Marathon will be transformational for us," Penrod said.