The executive direct of Cure CMD discussed the state of care for patients with congenital muscular dystrophies, the need for new treatments, and the patience with gene therapies.
This is a 2-part interview. Click here for part 1.
For many rare neurological disorders, growing a treatment profile is often the most important, but challenging objective. The rarity of these types of disorders, including neuromuscular diseases like congenital muscular dystrophies (CMDs), plays a factor in the ability to recruit patients for trials assessing potential treatments. Since it was founded in 2008, Cure CMD has been at the forefront for advancing global research, building community support initiatives, and improving the quality of life for patients with CMDs.
The organization focuses on the 5 primary subtypes of CMD: collagen 6, the alpha-Dystrogycanopathies, LAMA2, LMNA, and SELENON. In late January 2023, the organization launched its Research Roundtable (https://www.curecmd.org/2023-research-roundtable), a 10-month program that brings researchers, stakeholders, and patients with CMDs together. Throughout the series, participants can learn about science, current and potential future research, and agree on attainable, realistic goals based on priorities for symptom management.
Recently, NeurologyLive® caught up with Rachel Alvarez, executive director of Cure CMD, to discuss the treatment landscape for CMDs, and where improvements can be made. As part of a new iteration of NeuroVoices, she spoke on the need for improved awareness, early detection, and role neurologists play early in a patient’s life. Additionally, she spoke on the state of gene therapies, the challenges that remain, and why these approaches don’t do much for adults with CMDs.
NeurologyLive®: How would you assess the current treatment landscape for CMDs? Which areas do we excel at, and where do we need improvement?
Rachel Alvarez: Each of our 5 primary subtypes is at a different place along the treatment roadmap. For SELENON—which is probably our most rare—we're still trying to understand some of the basic pathologies. We haven't been able to spend a lot of time identifying treatments. LAMA2 is probably the furthest along amongst our 5 subtypes. We have pharma interest and there are people developing protein replacement therapies for that subtype.
It's hard because this is an extremely heterogeneous group of diseases. Within each subtype, the heterogeneity is broad, and the spectrum is incredible. And so, when trying to come up with a treatment for these conditions, you're almost stacking the deck against yourself before you even set out because there's just so much variability. We're trying to reduce some of that. We're trying to identify the key aspects within each subtype that are most impacting quality of life, morbidity, and mortality. We want to home in on those to help the maximum number of people within each subtype.
Additionally, there's been a lot of issues and concerns with some of the trials that have come out. For example: gene therapy trials, we've had people die. I still feel like we have a long way to go in terms of really understanding what can happen if you start messing with gene therapy. I know that families are eager to have treatments for their kids or for themselves, but I'm still hesitant. I think we still have a lot to learn, and a long way to go to ensure that these treatments are safe. Because the last thing we want to do is lose people because of participation in clinical trials.
Where do we currently stand with gene therapies in CMD?
I think everybody who's working on producing gene therapies for all these various neuromuscular conditions is well aware of the concerns and wants to make sure that this is a safe environment to work within. But it's hard when you have pressure from real people who want treatments now. Gene therapy is going to be most effective in infants and newly born. The earlier you can implement that kind of treatment, the better. And so, parents are pressing with great urgency watching their kids grow up and realizing they're not going to be great candidates for this. There’s push and pull to find a good balance, but safety must be prioritized above all else.
I know some parents who are willing to take whatever risk because they see this disease as a death sentence. All I can do is tell them that it's not [a death sentence]. If you're optimizing care, you're making sure that a child is engaged, making sure that they're getting everything they need—then you can live a great life with this condition. The focus should be on today and making sure that kid is happy and healthy, and not so much about getting that treatment and curing them. We need to be more realistic. If you're constantly stressed about what “could be,” you're missing what's happening right now, and that's what's important.
Do patients have enough access to genetic testing when they need it?
It's getting better. It's becoming more available, and there are a couple of companies who are offering free genetic testing. It's still two-fold problem for adults. For the most part, this has been a pediatric condition. Fortunately, because of good standards of care, people are living longer and into adulthood, myself included. Genetic testing wasn't a thing when I was born. I didn't get genetically confirmed until age 38, and it was a fluke that it even happened.
For kids, genetic testing is readily available. We're seeing kids getting diagnosed younger and younger, which is good, because that means we can implement the appropriate standard of care as early as possible and catch the things—pulmonary or respiratory failure early—that we need to take care of. But for adults, if you've been living with this condition your whole life and there wasn't genetic testing when you were in the pediatric system, there are not a lot of adult neurologists who are familiar enough with these pediatric conditions to believe that test genetic testing is important. They might say: “There's no treatment, so why bother finding out what the diagnosis is?” That's completely backwards. There is a very specific standard of care for each of these subtypes. Even if you are in the general bucket of congenital muscular dystrophy or congenital myopathy, that's not enough.
Some of these conditions elaborate cardiac complications. Some elaborate very early respiratory failure that can go untreated. Understanding a diagnosis, regardless of whether there's a treatment available, is critical to making sure that you're living your best life, and you're getting the optimized care that you need. Overall, for adults, it’s still tenuous at best trying to get genetic confirmation, but much better for kids.
Are CMDs included in the newborn screening process?
No, they're too rare, which is problematic. Like I said, the rarity is probably our biggest hurdle. Because each of these subtypes have a gene or multiple genes that can lead to one of these conditions. You can't test for CMD, you're basically testing for 30+ genes. If it's a myopathy, you're adding another 30 or 40 genes. Looking at all the pediatric onset neuromuscular conditions, there are 120 genes. Adding CMDs to newborn screening, on top of everything else, when it's 1 in a million chance, or 1 in 400,000 chance that this kid has one of these conditions, is not a priority of each individual state.
We have to hope that pediatricians and then neurologists are catching these signs earlier and applying panel tests. You could be a non-expert neurologist and use a panel test to try and make a direction, but you're still going to have to be able to interpret those results. Unfortunately, l of us have benign mutations in these conditions and being able to weed out what's causing the disease still requires a level of expertise that not a lot of people have.
Transcript edited for clarity. Click here for more NeuroVoices.