Roadblocks Faced by Gene Therapies for Muscular Dystrophies

John Brandsema, MD

Over the past few years, a number of new disease-modifying treatment options have become evaluable for neuromuscular diseases like Duchenne muscular dystrophy (DMD). This has presented a new challenge for treating physicians when multiple potential options, such as gene therapy and exon-skipping therapy, exist for a single patient.

Ahead of the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, scheduled for March 16-19 in Dallas, Texas, CGTLive®'s sister site NeurologyLive® recently spoke with John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, who will be the leader of the “Gene Therapy Updates” session, to learn more about ongoing challenges with treating patients in this field. Brandsema emphasized the critical need to identify the right candidates for the right treatments, and stressed that more data is needed to aid in these decisions.

NeurologyLive: Are there concepts or aspects about gene therapy that continue to stump us, or that we continue to have challenges with?

John Brandsema, MD: Yeah, so I mentioned, who's the right person, who's going to react, and then you mentioned combination treatment, and that's a whole other area of inquiry that's really important to be clear about. We now have the good fortune of having multiple targeted treatments for some of our diseases that we care for, and so we have to think about which sequence of interventions would be appropriate at which time. The other side of that is, of course, disorders where there really is no treatment other than supportive care right now and so gene therapy would be the first thing that we would be offering that is disease-modifying. That is a transformative thing when it happens, of course, but we haven’t really had that so much yet. It's been diseases that had other targeted treatments ahead of them that had gene therapy come in so far, at least in the pediatric space.

I would love to learn more about what the right conversation is to have with each individual person, and then the conversation becomes even more nuanced when you bring in factors such as newborn screening and early identification, right? We've certainly seen spinal muscular atrophy have a complete reversal, practically, of what we were doing in the clinic before. With early treatment and combination treatment in that space, we've had some outcomes that are quite astounding, but it's still not curative. But that is an example of a success story.

Then we have other diseases that we might be identifying earlier, like DMD, if that gets to the point of newborn screening universally across the country. There's already several pilot programs. But the question then is, "okay, so I know this person has DMD, what do I do then? Should I start steroids very early? Should I start exon-skipping therapy very early? Should I start gene therapy? And if so, when is the optimal time to do that relative to the development of the person and optimal effect?" I mean, these are all questions that many people have, and yet there's no answers right now based on our experience that we have so far.

Then at the opposite end of the spectrum, those who are studied in the trials are not like the people that we end up having the ability to dose in the real world a lot of the time. This has come up a lot in conversation—like the older person with DMD who is heavier and has less muscle relative to their overall body habitus because a lot of it has been replaced by fat and fibrotic tissue. Does that person warrant the same dose of gene therapy? Can we have the same expectation of what kind of efficacy would come of that and are there safety issues that are different? These are all conversations that are very active and need to be better understood with actual real world data rather than just guessing, which it feels like we're doing right now.

This transcript has been edited for clarity.