Ongoing Research Seeks to Address Challenges With Muscular Dystrophy Gene Therapy

Jeffrey Chamberlain, PhD

Although the FDA's approval of Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys) for Duchenne muscular dystrophy (DMD) revolutionized the field of neuromuscular disease, much work remains to be done. At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, numerous presentations were given on new approaches to treating DMD and real world use of Elevidys itself.

At the conference, CGTLive® spoke with Jeffrey Chamberlain, PhD, Professor, Neurology and Medical Genetics, and Adjunct Professor, Biochemistry, and McCaw Endowed Chair of Muscular Dystrophy at University of Washington, about which presentations stood out to him at the conference. Chamberlain noted studies covering safety risks of Elevidys and research that may be useful in addressing these risks.

CGTLive: Were you excited to see any specific talks or trends in research at MDA this year?

Jeffrey Chamberlain, PhD: There were a number of really exciting presentations made at the meeting. The advances that are coming along are not only in the study of different types of muscular dystrophy and the mechanisms that are leading to these diseases, but also different approaches for therapies. With my own interest being in gene therapy, I tend to gravitate towards the talks on gene therapy. There's a lot of exciting developments there. There's many different approaches now for gene therapy, even for DMD, but also increasingly for other types of muscular dystrophy. There were several very exciting talks about new mouse models and new, larger animal models for different types of muscular dystrophy. There's also a nice combination of basic mechanistic studies and how some of the newer therapeutics relate to that. [There are] some studies on new biomarkers for different types of muscular dystrophy that are really important for doing clinical studies because often the changes in actual strength of muscular dystrophy patients will change fairly slowly so having a biomarker, particularly a serum biomarker, can be a really fantastic way to get a preview of whether your interventions are having an impact.

But one of the exciting things is there have been developments in small molecule drugs that are having an impact on different types of muscular dystrophy; oligonucleotide therapeutics, particularly antisense therapeutics, that are having impacts; as well as new viral vectors and things of that nature. One of the things I thought was particularly exciting was some developments in lentiviral technology. Lentiviral vectors have traditionally just been used in stem cell therapies, particularly hematopoietic stem cell therapies. But there was a development by the lab of Doug Millay, PhD, [associate professor, UC Department of Pediatrics] where he's been able to make a myotropic version of a lentiviral vector that's looking remarkably effective at delivering large genes to muscle stem cells. I think that's going to be an important complement to many of these other therapies that are coming along.

What about the research on the real-world use of Elevidys?

Even though we now have an approved gene therapy for DMD, it's not a perfect drug. It seems to be the best thing so far and we're very excited about that. But there were a number of talks about some adverse events (AEs) that have been seen in some of these trials. One of the challenges for the muscular dystrophies is that even though we can now use these AAV vectors to deliver genes to muscle, it requires extraordinarily high doses, on the level of about 100 times higher doses than you need for liver gene therapy or other things like that. That's been associated in some patients (certainly not in all the patients) with some serious AEs, mostly related to activation of the innate immune response.

So there were discussions about which patients has that been seen in? What are the early signs of these adverse events? What are the best ways to get in there and try to reduce problems that may be associated with that? Then there were also several presentations on ways to maybe overcome that. One of the more exciting areas, I think, is that there are new generations of delivery vehicles; not only new types of AAV vectors, but also new lentiviral vectors that may be effective. We're hoping that these more potent delivery vehicles will allow us to lower the dose. I think that's going to be important for reducing some of the serious AEs that have been seen in the muscle gene therapy trials.

This transcript has been edited for clarity.

Click here to view more coverage of the 2024 MDA Conference.

REFERENCE
Muscular Dystrophy Association Announces Recipient of 2024 MDA Legacy Award for Achievement in Research, is Jeffrey Chamberlain, Ph.D., Leading Professor in Gene Therapy. News release. January 30, 2024. https://finance.yahoo.com/news/muscular-dystrophy-association-announces-recipient-145900986.html