The University of Rochester Medical Center (URMC) has received $8 million from the National Institutes of Health (NIH) to support pioneering research on muscular dystrophy. The grant, which is a renewal of URMC’s Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, will fund ongoing work to investigate the genetic mechanisms and progression of this complex multi-system disease, research that has led scientists to the threshold of potential new therapies for myotonic dystrophy.
“The mission of the URMC Wellstone Center is to promote research that leads to effective treatments for muscular dystrophy,” said Charles Thornton, M.D., a professor in the URMC Department of Neurology and director of the URMC Wellstone Center. “This new funding will enable us to continue a research program that has been forged from a true partnership between bench scientists, clinical researchers, and patients and their families.”
URMC is home to one of six NIH-designated Wellstone Centers in the nation. URMC was selected in the first cycle of funding when the program was launched 16 years ago and is the only Wellstone Center that has been continuously funded since the program’s inception. With the current award, URMC has received a total of $29.8 million in NIH funding to study the disease since 2003.
The URMC Wellstone Center focuses on myotonic dystrophy, a disease that can be lethal in infants and adults and is characterized by progressive disability. Researchers at URMC have been studying myotonic dystrophy for more than 30 years and their work has transformed our understanding of the biological mechanisms of the disease. The new funding will support a long-standing collaboration between researchers at the University of Rochester and RNA scientists at the University of Florida.
Approximately 40,000 Americans have myotonic dystrophy, which is one of the most common forms of muscular dystrophy. People with the disease have muscle weakness and prolonged muscle tensing (myotonia), which 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. Currently, there is no medication that can halt the progression of the disease.
More than a decade ago, several scientists, including Thornton, uncovered how a genetic flaw – a ‘stutter’ that results in thousands of repetitions of the genetic code on a segment of chromosome 19 – gives rise to the disease. In myotonic dystrophy, this defect results in the creation of an abnormal RNA, which accumulates in the nucleus of cells and interferes with the normal activity of many genes. This discovery was the first example in medicine of the toxic effect of RNA. Subsequent research has shown how this phenomenon contributes to other diseases and work by the Rochester and Florida teams has demonstrated how toxic RNA causes health problems.
This research has advanced to the point where it could lead to a potential new therapy to improve or prevent the symptoms of myotonic dystrophy. Partnering with Ionis Pharmaceuticals, the Rochester team developed a synthetic molecule – called an antisense oligonucleotide – that mimics a segment of the genetic code. In a study appearing in the journal Nature in 2012, Thornton and his colleagues showed that, when injected into mice with myotonic dystrophy, these molecules improved function. This treatment has now advanced to testing in people.
The new grant supports two projects that will be undertaken by a team of clinical and translational researchers at URMC – Thornton, Johanna Hamel, M.D., Mike McDermott, Ph.D., Rabi Tawil, M.D., Chad Heatwole, M.D., and Kate Eichinger, Ph.D. – and a team of RNA scientists and geneticists from the University of Florida – Maurice Swanson, Ph.D., Eric Wang, Ph.D., and Andrew Berglund, Ph.D.
One of the projects is employing the new gene editing technology CRISPR to create new animal models of the disease that will allow scientist to study with more precision the mechanisms of myotonic dystrophy and potentially other similar genetic diseases. Another project will follow a group of patients with myotonic dystrophy type 2, another form of the disease, to better understand how the disease progresses over time and develop biomarkers that will allow researchers to test the effectiveness of new treatments. Other projects are focused on developing new treatments for both types of myotonic dystrophy.
The new grant will also support the National Registry for Myotonic Dystrophy and Facioscapulohumeral Dystrophy, which was established by Thornton, Tawil, Richard Moxley, M.D., and their colleagues in 2000. This database, which now includes more than 2,200 people with these conditions, has been a critical research tool and has enabled researchers across the county to study the disease and recruit participants for clinical trials. The researchers credit the Registry and the close links formed with hundreds of patients, families, and advocacy organizations as instrumental in creating the foundation for the URMC Center’s research objectives.
“The URMC Wellstone Center is the embodiment of how we need to approach research and care for people with neurological disorders in an era when new genetic treatments are poised to transform how we treat these diseases,” said Robert Holloway, M.D., M.P.H., chair of the URMC Department of Neurology. “This has been a true partnership between scientists and patients and this dialogue has enabled us to learn from individuals with this complex disease and understand what aspects most impact their daily lives. Their priorities have set the tone.”