On the fifth floor of Children’s National Medical Center, in the southeast corner of a large lab, is a cubby with a desk, a computer, two bike helmets, and three phones. From this understated workspace, Eric Hoffman, Ph.D., directs one of the world’s largest centers for the study of genetic disorders — the Center for Genetic Medicine Research.
Hoffman, a family man who spends most of his free time outdoors, dislikes doors or walls in his workspace. He thinks academic medicine is too “siloed,” and believes that more openness means more collaboration. He explains his science by using metaphors of Slinkys, Tinker Toys, and cookbook recipes. He laughs a lot. It’s not yet 11 a.m., and Hoffman has already advised on a grant application, spoken with members of his lab, and interviewed a prospective nurse. Now, he is explaining a new treatment possibility for Duchenne muscular dystrophy, the disease that best defines his research and that lies closest to his heart.
Children’s National serves as the home of two GW School of Medicine and Health Sciences (SMHS) departments: Pediatrics and Integrative Systems Biology, which Hoffman chairs. Hoffman, who is also a professor of Pediatrics at SMHS, landed at Children’s National 10 years ago, after a long stint at University of Pittsburgh School of Medicine and several years of teaching and postdoctoral work at Children’s Hospital Boston and Harvard Medical School. He has been awarded fellowships from the Howard Hughes Medical Institute, the Muscular Dystrophy Association, and the American Heart Association. Now, he runs a lab that covers thousands of square feet and spans two floors, staffed by 35 faculty members and 200 researchers.
Duchenne is a muscle-wasting disease that strikes one in every 3,500 children, mostly boys. It is an X-linked recessive trait — carried on the X-chromosome and more commonly expressed in males — but, like dwarfism, occurs spontaneously more often than it is passed down. Typically, children with the disease develop normally for their first few years, and then begin to have trouble climbing stairs, getting up from the ground, or breaking into a run. Most are in wheelchairs by their teens, and as the disease progresses, eventually require respirators to breathe. The majority die in their 20s or 30s from heart failure. There is no cure.
Hoffman is one of the leading researchers working on a new treatment option for Duchenne called exon skipping. He has high hopes for the therapy, but worries that existing regulatory rules and overwhelming cost will slow efforts to get the drug approved and made widely available to patients.
“The real tragedy is if something works that can help these patients, and we can’t deliver it,” he says.
Hoffman’s interest in muscular dystrophy can be traced back to his postdoctoral days at Harvard, when he first began manipulating the genes of fruit flies, changing their eye color and turning their wings backward. He spent long hours in the lab and often took the flies home with him. One Thanksgiving, he stationed a jar of fruit flies beside his plate during the meal to be sure the flies weren’t having “inappropriate sex,” which might compromise his research. “Of course,” he recalls, “there’s only so long that you can turn their eyes [different] colors and their wings backward before you start to ask the question: How is this helping humanity?”
So he shifted his focus. Using what he’d learned manipulating genes, he turned his attention to human genomes. Soon after, his Harvard research team, led by Louis Kunkel, Ph.D., became the first to identify and clone the gene responsible for muscular dystrophy: the DMD gene.
It was 1986, and little was known about the disease at the molecular level. But suddenly, characteristics of muscular dystrophy that had baffled researchers began to make sense. Most genes have about 30,000 DNA units. The DMD gene, they found, had more than two million, making it the largest known human gene. Its sheer size made it more prone to spontaneous mutations, which explained why the disease was so common. And, researchers discovered, it coded for a protein critical to muscle function. They named the protein dystrophin.
The job of dystrophin is to reinforce the walls of muscle cells, which are long and tubelike, and which constantly stretch apart and slam together as people move. The dystrophin protein gets plastered along the muscle walls, providing the strength and support needed during muscle contraction. But mutations can cause the gene translation process to go haywire.
Genes are divided into exons and introns. Exons code for protein; introns, also known as “junk” DNA, are the stuff in between, and unnecessary for protein production. During gene translation, the 79 exons that make up a normal dystrophin gene are spliced from the gene’s introns and pieced together like a puzzle into messenger RNA (mRNA), which then translates into the dystrophin protein. When the exons are appropriately assembled, they form a reading frame in which each three-letter section of mRNA translates into one amino acid.
The structure of this frame is enormously important. If any part of any of these 79 exons is damaged or deleted through a mutation, then the message can get scrambled. This can prevent the mRNA from being assembled in a readable form, resulting in a nonfunctional dystrophin protein. Hence, Duchenne. “If you’re missing it, you start blowing holes in your plasma membrane,” Hoffman says. “And that’s the first key finding to diagnose a patient with Duchenne. You might actually see enormous amounts of muscle guts in their blood.”
Exon skipping drugs, a form of antisense compound that interact with nucleic acids to modify gene expression, are sometimes described as “molecular patches.” They seal and repair the damaged fragments of the mRNA. “What the exon skipping drugs do, in lay terms, is go into the genetic molecule, trim the ends around that deleted area, and splice them back together. And then the message makes sense again,” says Valerie Cwik, M.D., research and medical director for the Muscular Dystrophy Association. Exon skipping would not cure Duchenne, but researchers believe it could substantially reduce symptoms, by remodeling a Duchenne patient’s mRNA.
In 2000, two Washington lobbyists, Joel and Dana Wood, had a disturbing meeting with their son’s preschool teacher. “She was being overly emotional about our need to get him checked out,” Joel Wood recalls. “She’d taught hundreds of students and had never seen a child at the age of three who struggled to get up the stairs as much as James did.” They took him to Hoffman’s lab for a dystrophin identifier test. Within a week, they had the full diagnosis: Duchenne muscular dystrophy. James was missing exons 44 through 52.
“It’s a devastating diagnosis when it’s your child,” Joel Wood says. “And I think anyone faced with that pretty much takes an inventory of their resources and figures out what they can do.” Research for the disease was grossly underfunded, the couple discovered, and what little funding did exist was divided among three government agencies.
Only months earlier, Hoffman had transferred from the University of Pittsburgh to Children’s National in Washington, D.C., where he felt he would be better positioned to advocate for federal support. His initial goal, cloning the first Duchenne gene, had been realized, but he continued to feel a strong obligation to deliver something to patients and their families. “I am quite focused on bringing therapeutics to these patients,” he says. “These kids and their families are my bosses.”
As it turned out, Duchenne was getting only five percent of the amount of federal funding that cystic fibrosis received, Hoffman recalls: “It was dismal, and nothing was being translated to the patients.” Hoffman and the Woods mobilized their efforts. They worked with members of Congress to pass the MD CARE-Act (Muscular Dystrophy Community Assistance, Research, and Education Act), which mandated that the government devote more attention and capital to muscular dystrophy. They led a lobbying effort to secure $60 million from the Department of Defense. The Woods launched the Foundation to Eradicate Duchenne, which has raised more than $10 million.
“The scientific world was alien to me before my son’s diagnosis, and I think the political world was just as mystifying to Eric,” Joel Wood says. “But he has very sophisticated political skills. He has an amazing ability to speak in plain English and make things understandable.”
In the lab and in the clinic, studies are advancing, thanks in part to what Hoffman and the Woods accomplished on Capitol Hill. After studies on Duchenne mouse models and human cells indicated that exon skipping drugs could activate dystrophin production, Hoffman’s lab scaled up its research to study dogs with the disease. Duchenne in dogs is swift and fierce. The dogs usually get sick and die within six months.
The dogs in the study had a point mutation in exon 7 of their dystrophin gene. After roughly six months of treatment with exon skipping drugs, the dogs began producing dystrophin again, at about 20 percent of normal levels in all skeletal muscles. And by every criterion studied — walking, running, eating, and drooling — the dogs’ muscle movement improved.
Results have also been promising in humans. Early-phase trials showed that the drugs appear to trigger dystrophin production in human skeletal muscles with no serious side effects. In another still-unpublished but public trial, 19 boys were treated for 12 weeks with varying doses of exon skipping drugs. Responses were varied, but in one case, nearly 50 percent of muscle fibers tested positive for some dystrophin after treatment. “It’s the first time anybody’s been able to get appreciable amounts of dystrophin back into the muscle,” Hoffman says.
Some are more cautious. While most skeletal muscles responded well to the drug, delivery to the heart has been less effective, Cwik says. But Hoffman hopes to see future research confirm that higher doses can fix that problem.
Exon skipping research is pushing regulatory agencies to consider questions that may soon apply to other areas of personalized medicine as well. Each drug, for example, needs to be tailored to the exact spot on the gene where the mutation occurs. “You need different drugs for different patients with an already rare disorder,” Hoffman says. To avoid sending each drug variation through a lengthy approval process, researchers are working instead to get the drug approved as a class.
The cost is also daunting. Developing the drug to treat three dogs cost nearly $1 million.
But after 25 years of research, Hoffman says, DMD experts are finally building a good “racehorse. . . . It’s certainly the best place it’s ever been,” he says. “There’s a lot more rationale and knowledge going into this, and a much more coordinated international effort.”
In the meantime, Wood is hoping to get his son, now 13 and recovering from a broken femur, treated with exon skipping drugs as soon as possible. “I have great confidence that this has no significant side effects,” he says. “The alternative is a disease that’s got a 100 percent mortality rate.”
For now, the Wood family has to wait out the research and the regulatory process. “It’s a very tough thing, especially when your kid is suffering,” Wood says. “I know we’re going to get there. What I don’t know is whether it will come in time for my son.”