Breaking Down Oculopharyngeal Muscular Dystrophy: From Clinical Gaps to Genetic Gains

Matthew Wicklund, MD, FAAN

Muscular dystrophies are a group of genetically inherited disorders characterized by progressive muscle weakness and degeneration. They differ in age of onset, muscles affected, severity, and genetic cause, but all involve mutations that impair the structure or function of muscle fibers. Some of these muscular dystrophies, like Duchenne muscular dystrophy, have seen several significant changes to the therapeutic landscape in recent years, whereas others, like oculopharyngeal muscular dystrophy (OPMD) and facioscapulohumeral muscular dystrophy, are in the process of beginning their first notable drug trials.

OPMD, a disorder that typically begins after age 40-50, was a topic of conversation at the recently concluded Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16-19, in Dallas, Texas. As part of a larger “Lab to Life” track, a talk given by Matthew Wicklund, MD, FAAN, covered some of the preclinical and clinical research efforts for OMPD, highlighting progress in understanding the genetic underpinnings of the disease and how it might lead to future treatments.

Wicklund, a professor of neurology at the University of Texas Health Science Center San Antonio, brings years of clinical experience to the field, participating in over 35 multi-center trials in the areas of muscular dystrophy, amyotrophic lateral sclerosis, and myasthenia gravis. During an interview with NeurologyLive^®, he spoke about his presentation given, as well as the preclinical and early clinical progress, particularly with a gene therapy approach that combines RNA interference with gene replacement. Above all, Wicklund spoke on the challenges of translating knowledge into effective therapies and the limitations of current trial designs, including uncertainties around biomarker access, redosing, and long-term durability.

NeurologyLive: Can you give an overview of OPMD—its genetic basis and the key challenges in diagnosis and treatment?

Matthew Wicklund, MD, FAAN: OPMD stands for oculopharyngeal muscular dystrophy, and as the name suggests, it involves the eyes (oculo), throat muscles (pharyngeal), and muscle weakening (dystrophy). Patients develop ptosis, followed by dysphagia, and eventually proximal muscle weakness, especially in the legs.

It’s a late-onset condition, with symptoms usually beginning in the 40s or 50s. The cause is a trinucleotide repeat expansion in the PABPN1 gene. Individuals with 10 repeats are unaffected; 11 indicates a recessive carrier, and anything higher causes dominantly inherited disease.

There are regional pockets where OPMD is more common: Quebec, due to a French-Canadian founder mutation; the American Southwest, among Hispanic populations; and in Bukharan Jewish communities in Israel. Globally, an estimated 15,000–20,000 people live with OPMD across North America, Europe, and Israel.

The main challenge is that we don’t have a disease-modifying treatment yet. We manage symptoms—slings for ptosis, speech therapy and dilation or botulinum toxin for dysphagia, and, when needed, surgical myotomy. Unfortunately, we have no approved treatments for the progressive muscle weakness.

What recent preclinical work has shown promise in understanding OPMD’s mechanisms and guiding future therapies?

In OPMD, the expanded trinucleotide repeat leads to protein inclusions in muscle. One strategy under investigation is to produce only the normal PABPN1 protein, while silencing the abnormal version.

Preclinical models are exploring ways to do this, including CRISPR-Cas9, knockdown-replace techniques, and RNA interference methods to block protein production at the ribosome. Targeting RNA and translation machinery could be a viable path forward, and we’re seeing multiple strategies tested across that spectrum.

Despite this knowledge, why has it been difficult to translate into therapies?

It’s a big question, but part of the issue is timing and prior trial outcomes. A phase 2 study of trehalose showed early promise, but the phase 3 trial didn’t meet its endpoints, which slowed momentum.

Now, we're entering the gene therapy era. At this meeting, and previously at World Muscle Society 2023, we heard about a novel gene therapy strategy that includes a dual-action cassette—a healthy PABPN1 gene copy along with two interfering microRNAs to silence the abnormal version.

In preclinical studies, this was delivered via direct injection into swallowing muscles in beagles. In humans, they’re performing a surgical procedure to inject the therapy into the superior and inferior pharyngeal muscles—essentially “tattooing” the muscles. Early data in the first few patients suggests improved swallowing and quality of life over 2 to 6 months post-treatment.

How does the clinical community view gene therapy for OPMD? Are there preferred vectors or delivery approaches?

The current approach uses an AAV vector, though theoretically, other delivery vehicles could be used. Importantly, this is not a simple gene replacement—it’s a combo therapy. You can’t just add a good copy of the gene; you have to silence the bad one too.

This dual-function strategy—knockdown plus replacement—is smart. The FDA often requires direct muscle injections for proof-of-concept, and here they’re targeting a highly symptomatic area: the pharyngeal muscles. If it works there, it could pave the way for systemic delivery or additional injections into other affected muscles like the levator palpebrae.

Still, we face limitations. We won’t be sampling tissue from those muscles, so no molecular biomarkers or transduction data will be collected. We’ll have to rely solely on clinical outcomes, which the FDA prioritizes—but it leaves many of us researchers with unanswered mechanistic questions.

What’s the concern around durability, redosing, and long-term efficacy?

Durability is a major unknown. A therapy might work for 12–15 months, but what about 3–5 years? We’re optimistic based on animal data, but long-term human data is pending.

Another issue is redosing. Some animal models allow for repeat focal injections, others don’t. If this therapy gets approved, and patients lose benefit over time, can we redose them safely? That remains to be seen—and it's a critical piece of the long-term strategy.

Beyond gene therapy, are there any other clinical efforts or trials for OPMD currently in development?

To my knowledge, there are no other clinical-stage programs for OPMD right now. That’s why this gene-based therapeutic is so exciting—it’s finally something in humans. That said, we’ve always had decent symptomatic options: slings for ptosis, swallowing interventions, and multidisciplinary care to support function and quality of life. Even without a cure, we can make a meaningful difference for these patients.

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