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Scientists home in on cause of Duchenne gene therapy side effect

Duchenne muscular dystrophy, a degenerative disease mostly affecting young boys, is one of the top targets for gene therapy developers. Recently, however, the pace of research has slowed as reports of a worrisome side effect in a number of clinical trial participants have led to study halts and new questions.

Now, scientists may have some strong clues to the cause, due to an unusual collaboration between rival drugmakers competing to develop the first Duchenne gene therapy.

Patients who experienced the side effect — the main symptom of which has been accelerated muscle weakness —all had similar genetic mutations that triggered an immune response to the genetic material contained in the therapies, an analysis presented Tuesday at a top gene therapy conference showed. Researchers involved in the work described the reaction as most likely a “class effect,” meaning something shared across similar therapies.

Even though some patients with the highlighted mutations didn’t experience muscle weakness, the companies developing DMD gene therapies are now excluding new patients with those mutations from trials, said Carsten Bonnemann, a senior National Institutes of Health researcher who presented the analysis at the American Society of Gene and Cell Therapy meeting. The findings were previously disclosed in March at another conference and in a community webinar.

Pfizer, Sarepta, Solid Biosciences and the French non-profit Genethon contributed safety data to the analysis, which helped researchers identify the specific mutations. Pfizer’s research, in particular, was recently delayed by months as it tried to work out why there patients experienced muscle weakness. A participant in an earlier trial also died, which led Food and Drug Administration to impose a clinical hold on testing, although it’s not clear whether that case involved similar symptoms.

The FDA last month allowed Pfizer’s clinical trial to resume, but the company will now monitor patients in a hospital for a week after infusion. Sarepta has also reported a case of muscle weakness following treatment with its therapy.

The research presented Tuesday involved a total of five similar cases, which appear to have been sparked by disease-fighting immune cells called T cells. The five individuals developed symptoms between 24 and 42 days after receiving a Duchenne gene therapy. According to Bonnemann, that timeline is consistent with the interval between treatment and when key muscle-building proteins would be stimulated.