Assessing the Recent Progress in ALS at MDA 2023

Stanley Appel, MD

In a few short weeks, the Muscular Dystrophy Association (MDA) will kick off the 2023 iteration of its Clinical & Scientific Conference at the Hilton Anatole in Dallas, Texas, and virtually via live stream. The meeting is set to bring together a variety of stakeholders in neuromuscular disorders, including clinicians, researchers, patients, advocates, and industry.

In addition to its focus on emerging technologies in genetic medicine, this year’s meeting includes an extensive list of sessions in its amyotrophic lateral sclerosis (ALS) track, including a deep dive into the field’s improving understanding of ALS. This session will be chaired by Stanley Appel, MD, director of the Muscular Dystrophy Association ALS Research and Clinical Center and emeritus MDA board member, and director of the Ann Kimball and John W. Johnson Center for Cellular Therapeutics at Houston Methodist, and will include presentations from Clotilde Lagier-Tourenne, MD, PhD, and Clive Svendsen, PhD.

Ahead of the meeting, Appel spoke with NeurologyLive^® to offer some insight into the plans for this session, the comprehensiveness of the ALS track, and the latest in clinical care for this patient population. View the full agenda for the MDA 2023 Clinical & Scientific Conference here.

NeurologyLive: What should attendees expect from this meeting and the ALS session you’re chairing?

Stanley Appel, MD: Well, number one, I'm truly excited that the MDA is hosting this meeting. It's such an important conference that, in this year, is a great example of how you reach out to the broader audience in medicine about the importance of what neuromuscular disease means to patients, and how we're making great progress.

Within that context, I'm equally excited that the MDA decided to spend a full day on ALS. ALS is clearly one of the most difficult diseases with a great unmet need, and we've made such substantial progress. This is an opportunity to express the kind of progress, the directions we're going, and the excitement for our patients. We're really learning how to enhance the quality and length of life for our patients. That's extremely important. That's the major overall message that we want to convey: That this is about patients. This is about helping patients, and this is to help neurologists, as well as all medical doctors, nurses, and medical staff to help our patients.

Specifically, in the session that I will be chairing, we're going to deal with 3 major areas that we think are real advances. But I don't want to pass the opportunity to talk about the afternoon session on ALS, because the low-hanging fruit are the number of patients with specific genes that are altered, and what we're learning with so called antisense oligonucleotides (ASOs) with viral vectors and putting genes in. There is no better example than a neuromuscular disease called spinal muscular atrophy (SMA), where we made substantial improvements enhancements of length of life.

Back to this specific session which doesn't deal with gene therapy, but namely, our advances in ALS. We had the opportunity to pick 3 different areas to emphasize. The areas that I selected are:

1. Do we know something about how the cell is injured in ALS, and by the cell I mean, the motor neuron? And it turns out that the motor neuron has 2 components. It's got a cell body, and then what is called an axon that reaches out from the cell body to the muscle. We've learned that you can have the axon dying while the cell body lives, and yet, it doesn't attach to the muscle and doesn't function. We call that pathology of the axon, an axonopathy, and one of the speakers, Clotilde Lagier-Tourenne, MD, PhD, in fact, is going to be discussing some of her elegant work on alterations in some of the components of the axon that are impaired in ALS, and impaired in the 90% of the patients with ALS that don't have a specific gene that has been designated and how that causes cell death. Now, it's causing an axonal death. But the exciting thing about this is every one of the proteins that she will be discussing in this brief presentation is now a target for therapy with evidence in animal models that it might improve things. An exciting approach that needs to be presented.
2. The other speaker is one of the top stem cell people in the world, Clive Swenson, PhD, and he has been focusing on cell therapy with cells made from neural progenitor cells, or even from inducible cells, so called iPSCs. He is one of the leaders in this area, and he has been looking at the ability of putting a growth factor into the cell, and then giving it to patients. He did it in the spinal cord, and he is in the process of developing the approach to do it in the brain of patients with ALS. So, an exciting advance from stem cells to meaningful therapy.
3. The third is the area that I'm going to cover. I have been, for a number of years, talking about how neuroinflammation is driving the pathology in the pathophysiology of ALS. It turns out that one cell, called a regulatory T cell, is impaired in ALS and, in fact, that impairment enhances neuroinflammation. We have been focused on how do you normalize these T reg cells? How do you take these T cells that are dysfunctional in ALS, correct them, and have them suppress neuroinflammation? There are exciting ways that we've been able to do it, including some pilot experiments that really are promising in terms of giving us a suppression of neuroinflammation through these regulatory T cells.

So that's a once over quickly of three different areas, all of which are based on basic science that, in fact, have therapeutic, not just implications, but likelihood of improving in the next year or so—and our patients will be the beneficiaries.

What would you consider some of the highlights of progress that have been made in ALS recently, and what are you looking forward to seeing progress in these coming years?

Well, a couple of things. Beautiful paper, published by Tim Miller and the team on ALS and mutant superoxide dismutase. I'm hopeful and optimistic that there's an opportunity for the FDA to give us the go-ahead to apply that to more patients. That's obviously not in our hands, it's in the hands of the FDA, but I think the evidence is getting more and more powerful that it may be not the short-term, but what happens over a year or so. Then let me come to my cell therapy, whether it's taking a cell and putting genes in as Clive Swenson is doing that will help ALS. But I'm a big fan, as you could imagine, of suppressing neuroinflammation and the results from where we are in preclinical work say we're getting there. The application is promising. I see this year, 2023, as enabling us in smaller studies to show potential promise efficacy, and then in much larger studies, to provide something so we can really tell our patients we're getting there, we can assure you enhanced quality of your life.

Transcript edited for clarity. View the full agenda for the MDA 2023 Clinical & Scientific Conference here.