Clinical Translation of Oculopharyngeal Muscular Dystrophy Research

This is the second part of an interview with Matthew Wicklund, MD. For the first part, click here.

Matthew Wicklund, MD
Credit: UT Health

Mutations in the PABPN1 gene, leading to abnormal protein aggregation and subsequent muscle cell degeneration, are typically the cause of oculopharyngeal muscular dystrophy (OPMD), a rare, late-onset genetic disorder characterized by progressive muscle weakness that primarily affects the muscles responsible for swallowing and eyelid movement. Currently there are no FDA-approved therapies that target the root cause of the disease, but gene therapy is an area of interest for ongoing development.

CGTLive®'s sister site NeurologyLive® recently interviewed Matthew Wicklund, MD, a professor of neurology at the University of Texas Health Science Center San Antonio, who gave a talk on clinical and preclinical developments in OPMD at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19, in Dallas, Texas. Wicklund spoke about the challenges of tackling the disease and gave his view on the most promising potential method to address it with gene therapy.

NeurologyLive: What are some of the barriers of taking what we know about OPMD and translating it into therapy?

Matthew Wicklund, MD: There have been trials in the past and probably the largest was a trial with a drug called Trehalose. Unfortunately, the phase 2 was exciting and a phase 3 was not successful. Then there was this sort of pause until we got into this new gene therapy era and that's what we heard about at this meeting and actually we also heard about it at World Muscle Society last October. There is now a new technique where there's a gene therapy that has a cassette that includes a normal copy of the gene, but part of the transcript can produce 2 separate interfering micro iRNAs. So these microRNAs will interfere with the abnormal RNA transcripts and then you still have the normal copy. So it's sort of a knockdown and replace and that's a very interesting model that is currently in humans, after being used in beagles for swallowing. It's an interesting strategy where they're actually directly injecting. We didn't actually see the injection, but it's almost like a tattoo along these muscles—to under surgical procedure inject into the superior and inferior pharyngeal muscles, and the hope is that that will allow for better quality swallowing. I think there are now 2 or 3 patients that have been dosed for which we have some data. There is data saying that predosing, the swallowing is a certain level of abnormality and then postdosing, the [change] over 2, 4, and 6 months has been improved swallowing with better quality of life related to the swallowing.

From your perspective, what is the feeling amongst other clinicians who help patients with OPMD regarding gene therapies and genetic approaches? Are there any genetic based approaches or vehicles that we feel as though would be best for this type of disease?

The current model is to use an adeno-associated virus (AAV) vector with the transcript. But the challenge is that it does not have to be AAV. It is in this case, but it could be any delivery mechanism. The big challenge is it's not a gene replacement therapy (a gene transfer therapy) because you really cannot just give another copy because then you'd have 2 good copies and still have the bad copy producing all the trinucleotide repeats, RNA sequences that then develop occlusions and then you have degeneration. So it really is unique in that it's a combo therapy in this 1 cassette transcript. You have both the normal copy being replaced, and then you have the 2 interfering RNAs that are part of that transcript. I think that's what has taken a while. There are certain programs that are preclinical that have looked at just the interfering RNA strategy, others that have looked at other strategies, but it seems to be that the combination would work the best. It's, in my mind, a very smart move because the FDA usually will want to see a direct muscle injection before you move on to broader therapy. And in this case, it's a wise move to say "okay, usually we take a muscle that in somebody that's so weak, it doesn't matter if you lose it"—in this case, it's proof of concept would be that if it works in a single-muscle, direct injection into a muscle in need, then maybe you could think about either doing more systemic therapy or combination therapy, where you could do levator palpebrae in addition to the swallowing muscles. So I think you could either do multiple injections, or you could look at going to systemic therapy. But that's maybe a few years down the road because we still have to make sure that this works.

Click here for more MDA 2025 coverage.