Data Gaps Leave Long-Term Impact of Ex Vivo Gene Therapy in DMD Uncertain

At present, the FDA has approved a single gene therapy for patients with Duchenne muscular dystrophy (DMD): delandistrogene moxeparvovec (Elevidys; Sarepta Therapeutics). This therapy may be delivered through the use of an adeno-associated virus (AAV) vector. However, as trials with follow-up for AAV-mediated therapy have only just begun, Giulio Cossu, MD, FMedSci, FEAS, professor of regenerative medicine, University of Manchester, noted, questions about the intervention’s long-term safety and efficacy remain.

In this interview, Cossu explored the pressing safety considerations accompanying ex vivo gene therapy for patients with DMD. His presentation on the safety, efficacy, and affordability of DMD gene therapies took place on Monday, March 17, at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference held in Dallas, Texas.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

What are the primary safety concerns associated with ex vivo gene therapy for DMD?

The major concern for ex vivo gene therapy, and not only for muscular dystrophy, but most monogenic diseases, is insertional mutagenesis by lentiviral vectors. 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, indicating they have acquired some proliferative advantage, which could be indicative of future leukemia. In the case of hematopoietic stem cell or cancer, in the case of other kinds of cells. 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. Something that with hematopoietic stem cell is not possible, because they cannot be in-culture long term. And I think this is, in fact, the main concern.

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. And 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. That to me, leaving aside all the other points, lentiviral vectors are in there forever, and there are follow-up of 20 years for other patients; but 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.