Muscular dystrophy gene therapy at Penn shows promise in mice, dogs

For a disease with grim consequences that strikes a lot of children, it is hard to top Duchenne muscular dystrophy. Each year, at least 400 new cases are diagnosed in the United States, nearly all of them boys, and most will lose the ability to walk by age 12.

Yet more than 30 years after scientists discovered the genetic cause of the disease, the available medicines do little to slow its course. As their muscles weaken, patients ultimately lose the ability to breathe on their own, and few live much beyond their 30s.

A new genetic treatment in development at the University of Pennsylvania may offer a promising alternative. In a study published Monday, the authors said they had successfully treated mice and dogs with the condition by delivering a customized gene to their muscle cells.

Other research teams have developed genetic therapies to treat the disease, coaxing patients’ muscles to produce a crucial protein called dystrophin that they are unable to make on their own. Dystrophin is thought to act as a shock absorber in muscle cells, and without its cushioning effect, muscles soon deteriorate.

But the solution is not so straightforward as simply replacing a missing protein. Because patients’ immune systems have never encountered dystrophin, suddenly introducing it can trigger a dangerous immune reaction, said Hansell H. Stedman, senior author of the study published in the journal Nature Medicine. One patient in Pfizer’s muscular dystrophy trial was admitted to an intensive-care unit with an immune reaction, the drug maker said this year, though full details have not yet been disclosed.

Mindful of that risk, the Penn team opted to try replacing the missing protein with a different one called utrophin, which has a similar structure but is not expected to provoke the immune system. That’s because utrophin already is present in the body for other purposes, and human beings are exposed to it in utero, Stedman said.

So far, the results in mice and dogs suggest that utrophin’s structure is close enough to dystrophin’s that it can act as a genetic pinch-hitter, preventing muscle deterioration without setting off alarm bells in the immune system, the authors reported.

The findings drew an enthusiastic response from two prominent experts in the field, Oxford University’s Kay E. Davies and the University of Washington’s Jeffrey S. Chamberlain, who wrote a column in the same issue of Nature Medicine.

The authors “present an exciting, novel opportunity to potentially restore normal function to individuals with DMD without a possible immune response,” Davies and Chamberlain wrote.

A keen observer of Stedman’s research is Masterman High School senior Yuva Gambhir, who has the disease. Gambhir, who worked as an intern in Stedman’s lab in the summer of 2018, helped review the manuscript. He also contributed to a companion study that has not yet been published, and he serves as an unofficial patient ambassador for the lab.

Last week he helped Stedman and co-author Leon Morales explain the study results, pointing to slides from the leg muscle of a dog whose cells were given genetic instructions to make utrophin. The cells looked healthy and pink, while cells from the animal’s other leg, which had been treated with a dystrophin-based gene therapy, appeared degraded.

“You can see how much healthier the tissue looks,” the teenager said. “It’s so clear.”

The effect of the treatment also could be seen in the animals’ behavior. Treated mice were better able to hold onto a mesh screen than those that did not receive the treatment, for example. They also were much more able to stand up on their hind legs, which the scientists detected with an infrared beam.

The scientists administered the treatment to the animals by injecting them with a virus that was modified to carry the genetic instructions for making utrophin.

The reason that utrophin can be substituted for dystrophin is because the two proteins are evolutionary cousins, said Stedman, who in addition to his research duties at Penn is a surgeon at the Crescenz VA Medical Center in Philadelphia.

About 500 million years ago, when our fish-like ancestors lived underwater, the gene for a primordial form of dystrophin underwent a duplication. The instructions contained in these two copies have diverged somewhat since then — one mutating into the modern form of dystrophin, the other into utrophin. But they remain close enough that they can be used interchangeably, he said.

Stedman and co-author Tejvir S. Khurana, a professor of physiology at Penn’s Perelman School of Medicine, say their treatment is the molecular equivalent of replacing Eagles quarterback Carson Wentz with Nick Foles. “Utrophin knows the playbook,” Stedman said.

The utrophin that is produced by the engineered genes is a “micro” form of the protein, as the normal version is too large to fit on the virus, said co-author Morales, who has a milder form of muscular dystrophy. But structurally, it gets the job done.

“It has all the important binding elements,” Morales said.

The team, which also includes researchers from Children’s Hospital of Philadelphia and Texas A&M University, ultimately hopes to test the therapy in human patients, though regulators may first require additional studies in animals.

In many clinical trials, therapies that work in animals do not prove effective in human patients. But Stedman and his colleagues are optimistic in this case because dogs with muscular dystrophy are considered a close approximation of their human counterparts.

The Penn treatment is expected to be most effective in young patients who have not yet developed serious symptoms, so it may come too late for Gambhir, who navigates the halls of Masterman in a motorized wheelchair.

Still, he remains optimistic that other drugs in development will prove helpful, and he has become an ardent advocate for research.

The 18-year-old speaks each fall at a DMD fundraiser in Philadelphia called Blingo, which is scheduled for Nov. 16 this year. The agenda includes wine-tasting, which prompted Stedman to tease the teenager last week that he would not be old enough to have a sip.

Yet he is old enough to conduct scientific research, and he plans to be back in Stedman’s lab next summer, helping to find a cure.