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Expert comment: AAV-based therapies for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severe inherited muscle-wasting disorder caused by mutations in the dystrophin gene, which regulates the production of dystrophin, a protein that helps protect muscle fibres from damage during contraction. While gene therapies designed to restore dystrophin expression have transformed the outlook for the field, important questions remain about their long-term safety and effectiveness.
In an expert commentary based on their paper published in Gene Therapy, researchers from the University of Oxford, including Associate Professor Thomas Roberts the Institute of Developmental & Regenerative Medicine (IDRM), discuss the current state of AAV microdystrophin gene replacement therapies for DMD and the challenges facing the field.
Adeno-associated viruses (AAVs) are small, non-disease-causing viruses commonly used as delivery vehicles in gene therapy. In DMD therapies, engineered AAVs are used to transport genetic material into muscle cells, allowing them to produce a version of the dystrophin protein that is otherwise missing in patients with the disease.
Because the dystrophin gene is one of the largest in the human genome, delivering the full-length protein using conventional adeno-associated virus vectors is not currently feasible.
To overcome this limitation, researchers developed shortened “microdystrophin” versions of the gene that retain key functional regions while being small enough to fit inside AAV vectors.
“The development of microdystrophin therapies represents a major scientific achievement,” says Associate Professor Thomas Roberts. “The field has moved remarkably quickly from preclinical proof-of-concept studies to approved therapies. But there are still important questions surrounding safety, durability, and the extent of functional benefit that these therapies can provide.”
The review discusses the development of several microdystrophin programmes, including Elevidys, the first AAV microdystrophin therapy approved for DMD. Elevidys initially received accelerated approval based on evidence that it increased microdystrophin protein levels in patient muscle tissue, a surrogate biomarker considered likely to predict clinical benefit.
However, Roberts notes that interpreting the clinical data remains challenging.
“While some trials reported improvements in functional measures, the phase 3 study did not meet its primary functional endpoint, although several secondary measures of muscle function exhibited statisticallysignificant improvements,” Roberts explains. “Notably, these secondary measurements have served as primary endpoints in trials supporting other approved DMD therapies.”
The review highlights a broader challenge emerging across DMD therapeutics.
“An emerging theme with DMD therapeutics is that a biochemical signal (i.e. restoration of dystrophin protein) is not necessarily associated with functional improvement,” says Roberts. “We believe that this may be related to the timing at which treatment is initiated, with earlier treatments associated with better outcomes.”
The paper also examines safety concerns associated with systemic AAV delivery.
“While AAV itself does not cause disease in humans, systemic delivery at the high doses that are needed to reach all muscles carries immune-mediated and organ-specific toxicities,” Roberts says. “In recent years there have been hospitalisations, acute-liver injury events, myocarditis, and a small number of fatalities associated with AAV therapies, including for DMD.”
“These events highlight the risks associated with high dose AAV therapies, and underscore the need for safer, more effective therapies.”
The review further discusses challenges including immune responses to AAV, the challenge of re-dosing patients, and uncertainty surrounding long-term durability of the therapy in growing muscle tissue. Looking ahead, Roberts points to several approaches that may help improve future therapies.
“In the near term, improved AAV engineering, including optimized or novel serotypes and split-vector systems, may enhance delivery efficiency and potentially allow more complete dystrophin restoration in selected contexts,” he says.
“Ultimately, alternative vector platforms capable of delivering full-length dystrophin at lower systemic doses may be required to overcome current biological limitations.”
The paper, “AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects”, by Katarzyna Chwalenia, Vivi-Yun Feng, Nicole Hemmer, Hans J. Friedrichsen, Ioulia Vorobieva, Matthew J. A. Wood and Thomas C. Roberts, is published in Gene Therapy.