Setback in gene therapy for Duchenne muscular dystrophy as immune system emerges as key barrier

•  New research identifies the body’s own immune response as a critical and previously underappreciated barrier to success

• Early intervention at birth could prevent immune rejection

• There is a need for personalised immune screening before treatment

• These findings could have broader implications for gene therapy in other conditions

A new paper, published in Gene Therapy, raises serious concerns about the effectiveness of gene therapy for Duchenne muscular dystrophy (DMD), after the treatment failed to show significant benefit in a large-scale clinical trial. 

The findings suggest that the body’s own immune system may be undermining the treatment with gene therapy such as Elevidys (delandistrogene moxeparvovec) aimed at reintroducing the missing protein dystrophin, and potentially preventing it from having any therapeutic effect.

DMD is a devastating genetic condition that primarily affects boys. It causes relentless muscle breakdown, loss of mobility in early adolescence, and premature death. With no cure currently available, gene therapy has been viewed as one of the most hopeful paths forward.

Elevidys was granted expanded approval by the U.S. Food and Drug Administration in 2024, with expectations high that the therapy, designed to restore a critical muscle protein called dystrophin, would transform the lives of those affected. But the latest data from the Phase 3 EMBARK trial tells a more sobering story.

“The results were disappointing. The treatment didn’t lead to significant improvement in muscle function, and we believe the immune system’s reaction to the reintroduced protein may be to blame", said senior author of the GT paper, Professor Darek Gorecki from the School of Medicine, Pharmacy and Biological Sciences at the University of Portsmouth. 

Dystrophin is absent in patients with DMD, so when it’s reintroduced via gene therapy, the immune system may perceive it as a foreign protein, an antigen, triggering a response that eliminates muscle producing this dystrophin, which undermines the treatment.

Some patients may be especially prone to this kind of reaction. Risk factors include chronic muscle inflammation, exposure to small amounts of dystrophin via so-called “revertant fibres”, or the presence of reactive immune cells that escaped normal deletion in early development.

Professor Gorecki explained: “This immune response is a huge hurdle, but understanding it is also an opportunity, it means we can start to adapt the treatment to work with the immune system, not against it.”

The study outlines several key approaches to improve future therapies:

• Screening patients for immune risk factors before treatment.

• Treating newborns early, potentially before the immune system becomes reactive, a strategy that could promote lifelong tolerance.

• Developing targeted immunosuppressive or desensitising protocols for older patients to reduce the chance of rejection.

The research also highlights the complexity of DMD itself. Beyond muscle, dystrophin plays a role in the brain, bones, and other tissues and any meaningful treatment will likely need to reflect that systemic impact.

However, researchers remain hopeful. “This isn’t the end of gene therapy for DMD”, added Professor Gorecki. “It’s a wake-up call that we need to go deeper to tailor treatments to individual patients and tackle the immunogenicity head-on.”

The study adds to a growing understanding that even the most advanced genetic therapies will require a personalised, multidisciplinary approach and that the path from lab to life-changing treatment is rarely straightforward.