Where peak performance meets progressive disease

Hansell Stedman, MD, knows what's happening in his leg muscles as he sprints up a snow-covered hill and skates down the other side.

As a competitive cross-country skier, he draws on decades of athletic experience. But he also understands muscle at the molecular level—the identity of the muscle fibers powering his climb, for instance, and how these fibers switch to a less efficient metabolic pathway that produces lactic acid.

By working his legs, pushing them outward in strokes like those of an ice skater, rather than gliding down the hill, he also knows he can force his muscle cells to burn that lactic acid. This strategy, while painful, can power a second wind that will give him an edge on his competitors.

Stedman, a professor of Surgery at Penn Medicine, learned this and much more over four decades of studying muscle function in Duchenne muscular dystrophy (DMD), the disease that took the lives of his two brothers.

In the late 1980s, when Stedman was a surgical resident, geneticists identified the gene that is altered in DMD and determined its sequence. The discovery opened the door to finally understanding how the disease damages and eventually destroys muscle. Stedman recognized that the goal he and others had long sought—curing DMD—might be possible.

As a skier, not just a scientist, he saw an added benefit. “There's a dividend here,” he realized, “because it’ll allow me to compete in a muscle physiology-driven sport by understanding how to focus on what matters most in training and recovery.”

Stedman has been racing for 50 years, with the goal of competing in the Masters World Cup and Winter World Masters Games “as long as there’s any natural snow left,” while pursuing what he calls the “quest for the Holy Grail,” a cure for Duchenne muscular dystrophy. He has built a lab in the Pennsylvania Muscle Institute (PMI) at the Perelman School of Medicine in which muscle research and personal experience inform each other, a dynamic reflected in the people who have joined him. They include an elite rower who looked to her athletic training to design experiments, and a Penn senior with DMD who has been both researcher and therapy recipient. Together, they are working to give dystrophic muscles more resilience—in effect, to restore to them some of the durability that protects those of an athlete.

Two discoveries

In one of his earliest memories, Stedman recalls people in white coats asking him to climb stairs, lie down, stand up. While he took these movements for granted, his older brother was struggling with them. Years later, his younger brother began showing the same difficulties.

The gene responsible wouldn’t be identified until after he had lost both brothers. But once scientists pinpointed the malfunctioning DNA, they could find the protein it was supposed to produce: dystrophin.

Dystrophin isn’t directly involved in muscle contractions. Instead, it stabilizes and protects the structure of the muscle cell. In DMD, genetic mutations interfere with dystrophin production. Without it, muscle cells become prone to rupture, causing damage that destroys them.

But well before researchers determined the molecular origins of this condition that would shape Stedman’s professional goal, Stedman had discovered what became his lifelong athletic passion. Brutal winters in Boston during his undergraduate years at MIT froze the Charles River solid and buried cars in snow. A native of Atlanta, with only limited experience with snow, he skied over both snow-covered cars and the frozen river and fell in love with the sport.

Over the decades that followed, Stedman kept skiing while pursuing a cure. He came to Penn for surgical residency in 1984, and then joined the faculty at a time when Penn was actively recruiting researchers who would define the new field of gene therapy.

Because DMD causes progressive damage to muscle, Stedman knew that a cure would mean different things to people of different ages. By correcting the body’s inability to produce dystrophin, a curative gene therapy would stop the disease’s progression or prevent it entirely in those too young to have developed symptoms.

Gene therapy can silence, replace, or alter faulty genes, making it a powerful tool for genetic disorders like DMD. In the 1990s, Stedman’s muscular dystrophy research advanced to the point where a gene therapy trial was in the works. Then, in 1999, a participant’s death in an unrelated trial for a different disease forced much of the field to hit pause.

In the years that followed, progress resumed with numerous gene therapies receiving FDA approval. But safety concerns persist.

“One of the bitter lessons is that the difference between a curative experience with gene therapy and a lethal complication is usually driven by the immune response,” Stedman said. “We are now building on generous support from the PMI, the National Institutes of Health, and a Penn startup biotech company StrongHolt Therapeutics to address these issues head on.”

Specifically, Kasden drew on a phase in her training cycle when she and her teammates alternate between longer, low-intensity sessions on a rowing machine or bike and higher-intensity workouts running or rowing. She had the mice in her study run at a pace that would put them somewhere between the two, elevating their heart rates and working their leg muscles, but not too much.

Translating this strategy into a regimen for mouse-sized legs took significant trial and error. But the results were striking: Dystrophic mice treated with utrophin gene therapy ran at higher speeds for longer. What’s more, the therapy provided long-lasting protection against heart damage—“a major step” toward clinical trials, according to Stedman. He hopes to have a clinical trial launched in about a year, after additional rigorous work and careful review of the proposed trial by the FDA. To move the work beyond the laboratory, he co-founded the biotechnology company StrongHolt, named after his older brother, to help manage the manufacturing and regulatory issues for a clinical trial he hopes to see initiated within two years by colleagues at Children’s Hospital of Philadelphia.

Gambhir may have a second chance with another gene therapy, though the odds are long. For one thing, his immune system now makes antibodies against its delivery system, a consequence of the earlier treatment. But he remains hopeful, for himself and for others.

“I’m particularly interested in getting rid of DMD, so no one else has to deal with what I’ve gone through,” he said.

Kasden sees a throughline between athletics and research: endurance. While she arrived eight years ago, Stedman has been working toward a cure for nearly four decades.

“It’s like training,” Kasden said. “You just have to continue to show up.”