Myotonic dystrophy type 2 (DM2), a rare form of muscular dystrophy, can trace its origins to a meeting three decades ago in the Garvey Room on the fifth floor of Strong Memorial Hospital. Present at the regular gathering of neuromuscular researchers were Robert (Berch) Griggs, MD, and Richard Moxley, MD, two of the founding fathers of the University of Rochester Medical Center (URMC) Department of Neurology, and Charles Thornton, MD.
As was a common practice, a patient with a puzzling case joined the group that day. This individual demonstrated the well-established clinical symptoms of myotonic dystrophy but did not possess the genetic flaw associated with the disease. The question put to those in the room was whether this case–one of a growing number identified via a new genetic test—was a completely new disease, a flaw with the test, or something else. “There was a vigorous debate and a wager that involved a six-pack of beer,” said Griggs. “But no one can recall who was on the winning side of the argument and whether beer ever changed hands.”
In 1994, Griggs, Moxley, and Thornton published descriptions of three of these cases in the Annals of Neurology, thereby becoming the first to describe DM2. It was proposed at the time that the new disease be named for the trio, but they declined in recognition of other scientific teams around the globe that were arriving at the same conclusions, and the disease eventually came to be known as DM2.
A growing wave
The discovery of DM2 was the product of neuromuscular clinical and research programs first started in the 1970s by Moxley and Griggs. Later joined by Thornton, Rabi Tawil, MD, a leading authority on facioscapulohumeral dystrophy (FSHD), and David Herrmann, MD, an expert in inherited neuropathies, and others, the URMC neuromuscular team has been instrumental in creating the global research networks, partnerships with the patient community, pipeline of trained clinical researchers, and research tools necessary to study the disease and advance new treatments.
One of the centerpieces of these efforts is the National Registry for Myotonic Dystrophy & Facioscapulohumeral Dystrophy, created in 2000 and supported by the NIH-funded Wellstone Muscular Dystrophy Cooperative Research Center program. This detailed database of more than 2,600 people with these conditions has been an invaluable research tool and enabled researchers to better understand the natural history of the disease and recruit participants for clinical trials.
This long history and depth of expertise places URMC researchers at the center of efforts to accelerate the study and approval of a growing wave of genetic therapies for neuromuscular disorders that are already revolutionizing care. URMC researchers are playing a leading role in clinical research involving genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy, FSHD, and Charcot Marie Tooth disease.
“These treatments are predicated on the ability to target the right tissues. Recent advances have created a diverse set of ways to accomplish this. Parts of the body previously off limits can now be reached with surgical specificity to modify the action of one gene and have no impact on others,” said Thornton.
Unraveling the mystery of myotonic dystrophy
The underlying genetic cause of myotonic dystrophy type 1 (DM1), a trinucleotide repeat expansion located on chromosome 19, was discovered in 1992. However, it was only a little more than a decade ago that Thornton and others showed how this defect results in the creation of toxic RNA, which accumulates in the nucleus of cells and interferes with the normal activity of many genes.
In a study appearing in the journal Nature in 2012, Thornton and his colleagues showed how a synthetic molecule called an antisense oligonucleotide that mimics a segment of the genetic code restored healthy protein functions in cells. In collaboration with industry partners, the team has recently shifted to employ more effective and targeted drug delivery technologies that employ small interfering RNA, and some of this work is now in early-stage clinical trials.
“Reaching this point required an understanding of the fundamentals in these diseases, the underlying abnormal gene and why it causes disease, the creation of mouse models, identifying a good target for treatment, and developing something that can impact that target and show how it reverses disease,” said Thornton. “All this has taken more than 20 years to accomplish and all of those steps in myotonic dystrophy occurred here in Rochester.”
Johanna Hamel, MD, joined the URMC neuromuscular research group in 2019, after completing fellowships in both neuromuscular medicine and experimental therapeutics. Her research focuses on expanding our understanding of the underlying molecular mechanism in DM1 and DM2, how the diseases progress, and the effectiveness of clinical outcome measures and biomarkers. Critical to these efforts is creating the infrastructure for more individuals to participate in research remotely.
“Many questions about myotonic dystrophy remain unanswered and only a small fraction of people with this disease are involved in research. Remote studies allow us to connect with study participants via video conferences, ship them appropriate devices that measure function, collect genetic information, and improve the sensitivity of biomarkers,” said Hamel.
The patients’ voice in research priorities
Approximately 80,000 Americans have myotonic dystrophy, making it the most common form of muscular dystrophy. Its name comes from the term myotonia, a prolonged muscle contraction that makes it difficult to relax muscles after use. Eventually, many patients have difficulty walking, swallowing, and breathing. The disease can also affect the eyes, heart, and brain.
“Decades of research are helping to build a detailed picture of how these diseases progress over time. In addition, close collaboration with patients and families has enabled us to pinpoint the symptoms that are most important to patients, which is essential given the multisystemic nature of the disease,” said Chad Heatwole, MD, professor of Neurology and director of the Center for Health + Technology, and a leading expert in DM2.
In 2012, Heatwole leveraged these insights to create a patient reported outcome (PRO) measure for DM2. His team has since gone on to develop more than 160 regulatory-grade, disease-specific PROs now being employed by academic, industry, and government researchers around the globe to measure clinically relevant changes in health in response to therapeutic interventions during clinical trials.
The PRO tool for DM2 may soon be put to use in a new study involving recombinant human growth hormone and testosterone as a therapy for the disease. Results from Heatwole’s URMC-led open-label study of the same drug combination in FSHD showed that the treatment was safe and study participants experienced improvements in ambulation, strength, muscle mass, and disease burden. Heatwole speculates the treatment regime may also benefit patients with DM2 and other neuromuscular disorders.
“Future treatments will likely consist of cocktail therapies. You need to stop the genetic mutation, but you also have to come up with therapies that will improve function to get patients back to a normal state,” said Heatwole.
Transforming pediatric neuromuscular care
The future is now for children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). URMC pediatric neurologist Emma Ciafaloni, MD, was at the center of the clinical trials for newly approved gene therapies for both conditions.
SMA is a rare hereditary genetic disease caused by a mutation in motor neurons that disrupts the production of a protein critical to the function of the nerves that control muscles. Symptoms typically appear within six months of birth and include difficulty breathing, swallowing, speaking, and moving, leading to death by age two. In 2019, the FDA approved a new gene therapy that helps re-establish muscle control in children with SMA. Ciafaloni served on a panel overseeing data collection and safety for clinical studies of the new treatment and was an advisor to the company involved in the initial development of the drug.
DMD is a fatal condition found in boys and characterized by progressive muscle weakness, the symptoms of which appear at a young age and progress rapidly leading to significant disability. Eventually spreading to the heart and muscles responsible for breathing, the disease is often fatal by the time the individual reaches their 20s or early 30s.
The pediatric neuromuscular team at Golisano Children’s Hospital, which includes Ciafaloni, Sam Mackenzie, MD, PhD, and Bo Lee, MD, are involved in the EMBARK study, an international phase 3 clinical trial for a gene therapy for Duchenne muscular dystrophy. Ciafaloni also served on the data and safety monitoring board for the early stages of the clinical studies.
The muscle weakness associated with DMD is the result of a genetic defect in muscle cells that impairs the production of dystrophin, an important muscle-building protein largely missing in people with the disease. The new treatment consists of a single infusion that, via an associated adenovirus, delivers a functional “micro” version of the dystrophin gene that takes over the production of the protein.
“There are boys who have been receiving the drug as part of clinical trials for four to five years. Parents send me videos, and the ability to get off the floor, jump, and run is not something you typically see in a seven, eight, or nine year olds with Duchenne,” said Ciafaloni.
In June, the FDA granted accelerated approval of the drug for four and five year olds. The results from EMBARK study are expected by the end of the year, potentially resulting in expanded eligibility. Ciafaloni is helping lead efforts to have DMD added to the New York State recommended panel of newborn screenings, to catch the disease early when treatments hold the greatest potential. The state added SMA to the screening panel in 2018.
While advances in SMA and DMD have already arrived at the clinic and treatments for a number of other neuromuscular disorders are on the horizon, these approaches have opened the door for other even rarer single gene diseases.
Mackenzie, who joined URMC in 2021, is among the nation's leading experts in TANGO2 deficiency disorder, a disease that appears in early childhood, and can result in episodes of acute illness called metabolic crisis, heart arrhythmias, breakdown of muscle tissue, seizures, and intellectual impairment. Efforts to study the disease are in the early stages, but Mackenzie is working with a C. elegans model of the disease that he is hopeful can help uncover the cellular function of the TANGO2 protein and accelerate therapeutic development through high-throughput drug screens. He is also working with Hamel in mouse models of DM1 and helping develop a model of congenital myotonic dystrophy.
“I have the best job in the world, being able to see patients in clinic, help them through cutting-edge clinical trials, and spend the rest of the day watching things light up under a microscope," said Mackenzie. “It is impressive what this group has accomplished in neuromuscular medicine, and I feel very fortunate to be a small part of the Rochester tradition.”