ALS Gene Therapy to be Discussed at the 2023 Muscular Dystrophy Association Clinical & Scientific Conference

Matthew B. Harms, MD

Gene therapy is an emerging area of interest for treatment of amyotrophic lateral sclerosis (ALS), with multiple investigational products currently in development in clinical study. Several of these candidates will be discussed at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, set to be held in Dallas, Texas, March 19-22, 2023.

Matthew B. Harms, MD, associate professor of neurology at Columbia University, and medical consultant and care center director for the MDA, will be chairing a session at the conference entitled “Gene Therapy in ALS”. The session will be held from 2:00 PM to 4:00 PM on Tuesday, March 21, 2023.

In the lead up to the conference, CGTLive’s sister publication, NeurologyLive, spoke with Harms about the topics that will be discussed in his session, the aspects of the conference that he is most looking forward to in general, and the several investigational products that he will be paying close attention to in 2023.

CGTLive: From your perspective, what is the most exciting aspect of attending the annual Muscular Dystrophy Association Clinical & Scientific Conference?

Matthew B. Harms, MD: The Muscular Dystrophy Association scientific and clinical conferences are a highlight of my year because it allows me to interact with people who are studying very similar and highly related diseases, but not just the exact same diseases that I'm taking care of. I think there's an extraordinary power in that.

Increasingly, meetings are specialized and once we get in our silos, we're missing out on innovations and developments that are taking place in other spheres; we just don't have time to follow it all. So, one great thing about the MDA conference is that it brings together people studying neuromuscular diseases of all kinds to learn from one another. There's been a lot in the media about the benefits of multigenerational living: families with multiple generations under the same roof. The older folks are learning from the youth and the youth are learning from the older folks, and that sort of thing. I envision this conference along those same lines, basically allowing fields that are a little further ahead to relay their learnings back, groups that are behind to ask questions, and basically, it allows for a lot of really deep interaction and learning from across the disease spectrums.

How would you describe the current state of gene therapy as a potential treatment approach for amyotrophic lateral sclerosis?

We know that 15% of ALS patients have a causative gene mutation that's leading to disease. We've been encouraged as a field by gene therapy and other modulating technologies like antisense oligonucleotides. To be able to get into the nervous system and create lasting change, like we've seen in spinal muscular atrophy and like the clinical reports are showing for Duchenne muscular dystrophy and other pediatric neuromuscular diseases.

Taking that same optimism and moving it into ALS, we also have gene-modulating therapies that are in clinical trials and looking very encouraging for one of the most common ALS genes, the SOD1 gene, with many companies developing similar modalities and other modalities for other known ALS genes. I think what's not as commonly recognized is that some of these therapies have a good chance of working in non-genetic ALS or in ALS where we haven't yet found a gene mutation because they're addressing kind of a root factor that's shared by most ALS patients, as opposed to this specific gene mutation in one of these more common causative genes. So I think it's a very exciting time as we think about being able to manipulate the genome in order to accomplish what we think needs to happen to slow down motor neuron loss.

Can you give an overview of the "Gene Therapy in ALS" session you will be chairing at the MDA Clinical & Scientific Conference this year?

So for the first hour, we've assembled a group of drug companies and academic labs that are focusing on gene therapy or antisense oligonucleotide development for ALS. We've structured it so that we'll be hearing about developments for super rare disease mutations. Dr. Shneider will be discussing "Silence ALS", which designs patients specific antisense oligonucleotide therapy that is hopefully going to knock down the mutated copy of the chromosome, sparing the good copy. For rare mutations, we're going to hear from a representative from UniCare, who's developing an AAV anti-SOD1 true gene therapy delivered by viral vector. We'll also hear from QurAlis developing modulators of C9 and ATXN2, some of which are applicable even for people who do not have gene mutations because we think there's a link between ATXN2 and TDP-43, one of those central molecules for ALS.

Once we've heard from people who are developing the next generation of gene therapies for ALS, we're going to hear from a group of people who are going to tackle how to prepare our clinics for the likelihood that some some or all of these may succeed. We learn from the gene therapy rollouts in spinal muscular atrophy and the impending ones for Duchenne muscular dystrophy that we need to plan well in advance. So we're going to tackle in the second hour some of the clinical aspects that need to be addressed. So first, we'll hear about genetic testing guidelines. If these therapies work, we're going to need to be able to expand, who gets tested when they get tested, how rapidly the results come back, and what have you. Jennifer Roggenbuck, MS, LGC, will talk about our efforts to develop genetic testing guidelines in ALS, then we'll hear from myself, as we talk about how to interpret the mutations that we find—you don't want to give gene therapy to people who do not have a causative gene mutation in the gene, and it's not always clear when genetic testing takes place, how to interpret these mutations. So I'll talk about efforts by international collectives to come up with a better way to classify ALS genes and ALS gene mutations.

And then finally, when it comes to administering these medications, some of which can be very difficult and somewhat invasive to administer by spinal tap, with potential complications, how do we prepare our workforce to be able to administer it if it is approved? We'll hear from Jennifer Morganroth, MD, from University of Pennsylvania, who has done some projecting about how many additional spinal tap slots we need in our interventional radiology suites, how many additional genetic counseling visits we're going to need—basically, like how can we expand our workforce, ramp up, and prepare to be able to deliver gene therapy quickly and efficiently and cost-effectively to the people for whom it will benefit? That's how the session is structured, I think it will be quite lively to think about what's coming and then how we prepare for it, in that kind of 2-part format.

What are you keeping your eye on in terms of potential advances in the ALS space this year?

Before the FDA are 2 very big drugs: gene therapy with a minidystrophin for Duchenne muscular dystrophy and the anti-SOD1 antisense oligonucleotide for SOD1-related ALS. Approval of either of these would be a game changer in our field and so we're very much watching that. I think, if either of those or both of those are approved, it's not going to only have an effect on treating patients, but I think we'll see a ramp up in all of the pharmaceutical and biotech industries—kind of seeing what's possible, seeing that these diseases are actually treatable, that they're tractable problems. And I think that we'll see many companies streaming into this space to develop additional or complementary medications to ones that are headed towards approval.

I'm excited to hear about some of those advances in technology: How do we make better antisense oligonucleotides? How do we make AAV-delivered therapies safer? The innovations that are really coming up around gene therapy I think will be well-represented at the conference across the spectrum and worth tuning into if you join virtually, which is possible for this conference, or coming in person to Dallas to join us for the Muscular Dystrophy Association Annual Conference.

Is there anything in this space that you think isn't getting enough attention or that you'd like to see more conversation about this year?

I think one thing that comes up in the press a lot when any of these medications gets approved is the pricing. I think we have to figure out as a country, as a whole, how we're going to get to a place where the prices for these advanced medications, which can be transformational, don't put them out of reach for the people who need them. And I think that's a very complicated discussion involving industry and government organizations, like the Muscular Dystrophy Association, that are always lobbying on behalf of patients and doing their best in the advocacy space to try to control drug costs. I think it's an important discussion and one that we need to hold people's feet to the fire on to make sure that we're providing equitable access to these very expensive, but potentially life-changing, medications. And not just here in the United States, you know, we need to be thinking globally.

Transcript edited for clarity.