For decades, neurologists caring for patients with myotonic dystrophy type 1, a genetic condition that affects the muscles and other organs in the body, have focused on managing symptoms rather than changing the course of the disease.
Adam Comer, MD, assistant professor of clinical neurology, is working to shift that reality by leading multiple industry-sponsored clinical trials at the Indiana University School of Medicine.
Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder that primarily affects muscle strength, function and control. While it most commonly affects the muscles of the face, limbs and respiratory system, adults living with the disease may also experience abnormal heartbeat, breathing complications, cataracts, gastrointestinal problems and cognitive symptoms.
“DM1 is the most prevalent adult muscular dystrophy, and we think of it as a multi-systemic disorder because it affects the entire body,” said Comer, who serves as the co-director of the Myotonic Dystrophy Clinic at Indiana University Health, the first of its kind in Indiana.
The root cause of myotonic dystrophy is a genetic mutation that causes cells to produce an abnormal, toxic form of RNA. This toxic RNA clumps together inside the cell and traps an important group of proteins called MBNL proteins, which normally help regulate how genetic instructions are processed. When these proteins are trapped and unable to do their jobs, Comer said cells begin to malfunction, ultimately leading to symptoms of the disorder.
More than 3 million people worldwide are affected by the disease, according to the Muscular Dystrophy Association.
There are currently no disease-modifying therapies to cure myotonic dystrophy type 1.
“There’s nothing that acts on the muscle to restore function either with respect to strength, myotonia or in any other way,” Comer said. “We have medications that may help treat symptoms of myotonia, but nothing that changes the course of the disease.”
What it’s like living with DM1
Many patients first begin noticing symptoms in their 20s and 30s, Comer said. Motor symptoms may be the first sign, while others may develop cataracts decades earlier than the general population, which typically develops them in their 60s or later.
Sixty-one-year-old Laura Moriarity from Carmel, Indiana, was clinically diagnosed with myotonic dystrophy when she was 26 after noticing muscle weakness in her hands.
She had trouble lifting heavy objects and said it took a while for her hand to open or relax after a tight squeeze, which is one hallmark sign of myotonic dystrophy known as grip myotonia.
Her sister, who, at the time, worked at the University of Iowa Health Care Medical Center alongside Laurie Gutmann, MD, chair of the Department of Neurology at the IU School of Medicine, was researching the hereditary risk of myotonic dystrophy and helped connect Moriarity with specialists.
“They noticed weakness in my pinky and recommended I see a neurologist when I returned to Indiana,” she said. “An EMG later suggested I had a mild case. I was officially diagnosed through a blood test in 1996, after my fertility doctor referred me to a genetic counselor.”
Over the years, Moriarity’s symptoms progressed and impacted other parts of the body.
There are times when her tongue “locks up” and makes it difficult to talk without words coming out as gibberish. Moriarty also experiences extreme fatigue throughout the daytime, and she can no longer run or even stand on her tiptoes when grabbing things.
“It’s a hard disease,” Moriarity said. “I’m fortunate that at least my symptoms are mild, but my heart goes out to people that are struggling daily more than I am.”
‘Part of the solution’
Comer is the primary investigator for HARMONIA and co-primary investigator for ACHIEVE, both run by Dyne Therapeutics to test the efficacy, safety and tolerability of zeleciment basivarsen for the treatment of myotonic dystrophy type 1 in adults and children age 16 and older. The drug is being studied globally in ACHIEVE, an early phase clinical trial, and then in HARMONIA, a confirmatory trial.
The drug studied in the ACHIEVE and HARMONIA trials consists of an antisense oligonucleotide that is carried by a specific fragment that can enter the muscle and central nervous system through a receptor present in those tissues. It’s designed to improve function in people living with myotonic dystrophy type 1 by reducing toxic nuclear RNA to release splicing proteins and allow normal mRNA processing.
ACHIEVE’s main goal is to see whether the treatment improves myotonia in the hand after six months compared with a placebo. The goal of HARMONIA’s trial is to see if treatment improves lower extremity strength, balance and trunk strength using a sit to stand test as the primary outcome.
The IU School of Medicine was the first site activated in the United States and the first to enroll a participant in both ACHIEVE and HARMONIA, said Lauren Perrey-Moore, RN, clinical research manager for the Department of Neurology. Five participants are enrolled at IU in ACHIEVE — the most for any U.S. site — and two are enrolled so far in HARMONIA, which continues to be open for enrollment.
“Both trials include a set of rigorous inclusion and exclusion criteria, as well as several assessments to complete by the research coordinators and physical therapy team,” Perrey-Moore said. “Recruitment into clinical trials is what determines the success of a new therapy to help people globally.”
Moriarity is one of Comer’s patients participating in ACHIEVE at the IU School of Medicine.
She said she chose to participate in the clinical trial because she wants to “be a part of the solution” and provide hope for others living with myotonic dystrophy.
“I have participated in other types of clinical trials with my dad, and my sister works in medicine — our whole family has always been firm believers in research, supporting healthcare workers and doing anything that we can do to help,” said Moriarity, who reports that her symptoms have improved since participating in ACHIEVE.
“In terms of my branch of the family, this disease stops with me,” she said. “All of my kids are either my bonus kids or adopted. After I found out I had it, I knew I wasn’t going to risk passing it on. But anything I can do while I’m here to help future generations — why not? That’s a no-brainer to me.”
Delivering the highest level of care
Comer said interest in these clinical trials has been so strong that patients have contacted the IU team from neighboring states and across the country seeking enrollment opportunities.
“There are always some unknowns in research, but there’s also a lot of regulation and monitoring,” he said. “That’s one of the benefits of being part of a clinical trial — you’re getting frequent labs and close monitoring.”
Clinical research is only one part of IU’s approach to caring for people with myotonic dystrophy.
Through the Myotonic Dystrophy Clinic, patients are evaluated by an array of specialists with expertise in the complexities of the disease, including neurology, pulmonology, cardiology and physical and occupational therapy. Team members consult and collaborate with other neuroscience specialists to create an effective treatment plan that is specifically tailored for each patient.
“We’re able to provide care from specialists who see these disorders all the time and understand their nuances,” Comer said. “Our patients receive the highest level of multidisciplinary care.”
Comer said the growing pipeline of clinical trials represents a significant shift for a disease that has long lacked effective treatment options.
“Myotonic dystrophy is a disorder we’ve been treating for a long time,” he said. “To now be able to participate in therapies that have a real chance of working is incredibly gratifying, and I’m excited to see the landscape change for our patients.”
