Researchers at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference in Dallas highlighted significant advances in gene therapy approaches for neuromuscular diseases, while acknowledging important challenges that remain in the field.
Transformative Potential of AAV-Mediated Gene Therapy
Dr. Barry Byrne, pediatric cardiologist and director of the Powell Gene Therapy Center at the University of Florida, described how adeno-associated virus (AAV)-mediated gene therapy has revolutionized treatment approaches for neuromuscular conditions, particularly Duchenne muscular dystrophy (DMD).
"The mechanism of action of AAV-mediated gene therapy is dependent on the strategy being used for the type of disease that is being treated," explained Dr. Byrne. For recessive diseases, the approach focuses on adding functional genes to affected cells, while for dominant conditions like facioscapulohumeral muscular dystrophy (FSHD), the goal shifts to reducing expression of pathogenic proteins.
Dr. Byrne emphasized the versatility of current gene therapy tools: "It's really an amazing toolbox now of AAV-mediated gene therapy to either add a gene, silence a gene, or edit a gene. This covers really almost every cause of neuromuscular disease."
A key advantage in treating neurological conditions is the potential durability of treatment. As Dr. Byrne noted, "In neuromuscular diseases, this might be either neurons or muscle cells. But the advantage of gene transfer for recessive diseases in neurons, as was done for spinal muscular atrophy, is these cells don't continue to divide after birth, and the gene transfer is effectively permanent."
Current Landscape of DMD Gene Therapy
The FDA has approved delandistrogene moxeparvovec (Elevidys; Sarepta Therapeutics) as the first gene therapy for patients with DMD. This therapy utilizes an AAV vector delivery system, representing a significant milestone in treatment options for this devastating condition.
However, Dr. Giulio Cossu, professor of regenerative medicine at the University of Manchester, highlighted important knowledge gaps regarding long-term outcomes. "The follow-up for AAV-based trials are only now beginning to be measured, so we don't know how long a nonintegrating vector will stay and produce the needed protein," Dr. Cossu stated during his presentation on safety, efficacy, and affordability of DMD gene therapies.
Safety Considerations Across Gene Therapy Approaches
Different gene therapy approaches carry distinct safety profiles. For ex vivo gene therapy using lentiviral vectors, Dr. Cossu identified insertional mutagenesis as the primary concern, though he noted modern techniques can mitigate this risk.
"Today, however, there are methods that allow us to measure where the vector is inserted into the genome and to see whether there are predominant clones with the same insertion sign and takeover," Dr. Cossu explained. "I would say it's not a major concern, because, especially in the case of cells that are grown in culture, you have all the time to look at this before you transplant the patient."
For AAV-mediated therapies, the safety profile differs. "In the case of AAV, there is a significant toxicity at a high level of vector necessary to achieve a proper expression of the transgene," Dr. Cossu cautioned. "This has been associated with quite severe toxicity, which now seems to be under control, but still once if something is there, there's not much you can do other than trying to manage the patient clinically."
Future Directions and Remaining Questions
While gene therapy approaches show tremendous promise for neuromuscular diseases, significant questions remain about long-term durability, safety profiles, and optimal delivery methods. The field continues to evolve rapidly, with researchers working to address these challenges while expanding treatment options for patients with previously untreatable conditions.
The ongoing clinical trials and emerging data will be crucial in determining the long-term impact of these innovative therapies on patients with DMD and other neuromuscular disorders. As Dr. Cossu noted, the field is still in its early stages of understanding the full potential and limitations of gene therapy approaches in these complex conditions.
