Bustling Gene Therapy Pipeline for Neuromuscular Diseases Brings Thorny Questions to the Clinic

As the number of gene therapy options to treat neuromuscular diseases like Duchenne muscular dystrophy (DMD) and spinal muscular atrophy grows, so will the need to strengthen the delivery infrastructure, understand the risk-benefit calculus, and gather data across age groups, according to panelists speaking at a session of the 2025 Muscular Dystrophy Association Clinical & Scientific Conference in Dallas, Texas. Session chair John Brandsema, MD, a pediatric neurologist at Children's Hospital of Philadelphia (CHOP), noted the packed room of attendees, which he called “a testament to how much interest there is in this area currently.”

Gene therapies approved based on trials with small sample sizes are now being made available to broader populations, leaving clinicians to help patients extrapolate the risks and benefits. | Image Credit: © RFBSIP - stock.adobe.com

Susan Matesanz, MD, medical director of clinical in vivo gene therapy at CHOP, made the case that the science may have outpaced the logistics, as gene therapies approved based on trials with small sample sizes are now being made available to broader populations, leaving clinicians to help patients extrapolate the risks and benefits. The challenge in this rapidly shifting field is “practicing medicine by press release,” so Matesanz called for academic-led long-term follow-up registries so that treatment centers can learn from one another’s experience. She also highlighted the importance of collaboration: At CHOP, for instance, the multidisciplinary gene team meets to share knowledge and decide next steps, and they are moving toward multicenter collaboration to work with a larger pool of data.

Experiences so far have yielded important lessons on the infrastructure needed to deliver gene therapies in the real world, and the steps are much more complex than they might seem at first glance. Every small detail, from preparing the electronic health record templates to ensuring the pharmacy has the right equipment to handle the therapy, must be seen to, and this complexity leads to equity issues in which access is not uniform across the US. Matesanz also pointed to some concerning gaps in current policy, like the absence of clear biosafety or handling guidelines and the lack of a national requirement for informed consent.

“These therapies are once in a lifetime, irreversible. You have to sign a consent form to receive a pint of blood, but you don’t have to sign a consent form to receive an [adeno-associated virus] gene therapy, which is a little crazy,” Matesanz said. To address this, her group at CHOP worked with their legal team to develop a template explaining the benefits, alternatives, and the known, potential, and theoretical adverse effects.

Wrinkles with accepting out-of-state Medicaid plans are also an issue as rural patients may need to cross state lines to the nearest treatment center, which presents an opening for policy reform. But for the clinicians in the audience, Matesanz emphasized the importance of sharing real-world data across institutions, which is especially important to combat the small sample sizes of current trials. “Our real-world data are going to get increasingly messy as we have more therapies, and that’s going to be a challenge that we’re all going to have to face,” she concluded.

The growing gene therapy pipeline also creates the need for complex discussions with patients and their families, according to the next speaker, Diana Bharucha-Goebel, MD, director of the neuromuscular program at Children’s National Hospital in Washington, DC. Currently, redosing is not possible, so the conversation about whether and when to try gene therapy must be approached with extreme care and consideration of not just the patient’s clinical factors—ambulatory status, DMD gene deletion, and the like—but also the pragmatic considerations of what trials they may be eligible for, whether that trial has spots available, and if the family is able to travel to participate in a trial.

“You might want to think about, in the discussion with family, how do they feel about gene replacement strategies that are under clinical investigation vs approved,” Bharucha-Goebel explained, using for example a case study of a young boy with DMD and cardiac involvement. “If you wait [for a therapy to be approved], will the cardiac disease continue to get worse, where that risk-benefit calculus really tips more unfavorably for that individual?”

These are not easy questions for anyone to answer, and they will require discussions lasting longer than the allotted 30-minute time slot, so clinicians need to dedicate time and ensure administration buy-in for the many calls and visits to make sure families feel informed about this irreversible decision.

“Making sure that family’s set up for the follow-up they need, regardless of what strategy you choose, is extremely important to keep safety of that child at the heart of that decision,” Bharucha-Goebel concluded.

While much of the research and discussion around gene therapies for neuromuscular diseases has focused on pediatric patients, this scope is set to widen, said Emma Ciafaloni, MD, FAAN, professor of neurology and pediatrics at University of Rochester Medical Center. When considering gene therapy, adults are “not just big kids,” she explained, because DMD decreases the muscle mass/body weight ratio over time, which correlates with age and ability to ambulate, such that nonambulatory patients with DMD have 55% higher body weight but 54% lower percentage of muscle mass than their ambulatory counterparts.¹

At this point, most of the data on gene therapy for adults come from the ENDEAVOR trial (NCT04626674) of delandistrogene moxeparvovec (Elevydis; Sarepta), which showed that a small cohort of adult patients with DMD had similar dystrophin levels after treatment were similar to those of the younger cohorts and no difference in vector genome copy per nucleus across age groups. Further data are expected from the phase 3, multinational ENVISION trial (NCT05881408),³ which is still enrolling patients and will bring “an opportunity to have more data to learn about how to have this discussion with our adult patients,” said Ciafaloni.

In the meantime, information about a patient’s cardiac function and pulmonary reserve is important for advising their choice on gene therapy, especially because potential adverse effects such as vomiting can be much more dangerous for an older, nonambulatory patient at risk of aspiration due to their pulmonary functioning.

“In real life, the decision is up to us, to the providers and our [patients’] family, and it's really based on comfort level, how much we feel comfort extrapolating from the current data and the principle about gene therapy that we know,” Ciafaloni said. She also predicted that gene therapy in adults will benefit greatly from next-generation nonvector delivery methods.

References

1. Evans WJ, Hellerstein M, Butterfield RJ, et al. Reductions in functional muscle mass and ability to ambulate in Duchenne muscular dystrophy from ages 4 to 24 years. J Physiol. 2024;602(19):4929-4939. doi:10.1113/JP287069

2. Zaidman CM, Proud CM, McDonald CM, et al. Delandistrogene moxeparvovec gene therapy in ambulatory patients (aged ≥4 to <8 years) with Duchenne muscular dystrophy: 1-year interim results from study SRP-9001-103 (ENDEAVOR). Ann Neurol. 2023;94(5):955-968. doi:10.1002/ana.26755

3. Muntoni F, Mercuri E, McDonald C, et al. P47 ENVISION, a phase 3, randomized trial evaluating the safety and efficacy of delandistrogene moxeparvovec in Duchenne muscular dystrophy: study design. Neuromusc Disord. 2023;33(suppl 1):S70. doi:10.1016/j.nmd.2023.07.028