The National Institutes of Health announced recently a second phase of the Rare Diseases Clinical Research Network totaling $117 million which includes funds for 19 research consortia.
Wayne State University received a five-year, $6.25 million research consortium grant from the National Institute of Neurological Disorders and Stroke under this program. The grant, “Inherited Neuropathies Consortium,” is an international project aimed at developing a better understanding of and new treatments for the various forms of Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is one of the most common genetic nerve diseases, affecting 1 in 2,500 people, or 120,000 Americans. CMT causes progressive muscle weakness, painful foot deformities and walking difficulty. As the disease progresses, weakness and muscle atrophy occur in the hands, resulting in difficulty with fine motor skills. Symptoms vary from patient to patient, with pain ranging from mild to severe, with some patients relying on foot or leg braces or other orthopedic devices to maintain mobility. To date, no effective therapies are available for any form of CMT.
To address this issue, Dr. Michael Shy, M.D., professor of neurology in the School of Medicine, and resident of Bloomfield Hills, Mich., is leading the study which aims to provide insights into disease mechanisms, develop therapies and educate future research on inherited neuropathies such as CMT.
According to Shy, there are mutations in more than 40 different genes causing CMT in millions of patients throughout the world. “Modern genetics and cell biology make developing treatments for these disorders a realistic possibility,” said Shy. “However, many of the individual forms of CMT are rare, so to better understand the different forms of CMT and develop rational treatments for them requires national and international collaborations between neurologists and scientists.”
The project has specific goals geared toward establishing a Rare Disease Clinical Research Center (RDCRC) for the inherited neuropathies. In particular, the group will determine the natural history of the most common forms of CMT that currently lack this information.
“At Wayne State, we have pioneered the natural history studies for the two most common forms of CMT – CMT1A and CMTX,” said Shy. “Our results are used by neurologists around the world to design clinical trials for these disorders. However, for the types of CMT to be studied in this project, we do not see enough patients at WSU to perform natural history studies by ourselves, hence the critical nature of having a national and international collaboration.”
In addition, the project aims to identify ‘modifier genes’ in CMT1A, the most common inherited neuropathy. CMT1A comprises about half of all the patients with CMT and is caused by an identical genetic mutation in all patients.
In collaboration with the Human Genomic Institute at the University of Miami, the group will use 21st century gene sequencing techniques to identify these modifier genes that will help determine how severely patients will be affected. Using the same techniques, the University of Miami researchers will identify the genetic cause of CMT in families in which only a few members have been affected, something previously not possible.
The project also will study children affected by CMT. The consortium will develop a pediatric scoring system that will be used around the world to measure impairment and progression of disability in children with CMT. The collaborators also will establish a new CMT Web site to provide patients, their families and scientists around the world with the latest CMT information. In addition, the consortium will carry out an international training program for clinical and research doctors to train the next generation of researchers for CMT and other neurodegenerative diseases.
Wayne State University has one of the largest and most comprehensive CMT programs in the world. The program is translational, combining patient care and patient clinical research with animal and cellular models of CMT. Since 1996, WSU has evaluated more than 1,200 patients with CMT from more than 21 countries, five continents and 46 states in addition to Michigan, with funding coming from the National Institutes of Health, Muscular Dystrophy Association and Charcot-Marie-Tooth Association.
Along with Shy, project collaborators include Gyula Acsadi, M.D., Ph.D., associate professor of neurology at WSU and director of the Pediatric MDA Clinic and Pediatric Neurology Clinical Division Chief at Children’s Hospital of Michigan; Steve Scherer, M.D., Ph.D., William Kelly professor of neurology and vice chair for research in neurology at the University of Pennsylvania; Mary M. Reilly, M.D., director of the neuropathy clinic at the National Hospital for neurology and neurosurgery in London, England, and head of the Peripheral Neuropathy component of the MRC Centre for Neuromuscular Diseases at Newcastle University and the National Hospital for Neurology and Neurosurgery; Francesco Muntoni, M.D., professor and consultant in paediatric neurology in the Dubowitz Neuromuscular Centre at the University College of London Institute of Child Health; Stephan Zuchner, M.D., associate professor of medicine, Miami Institute of Human Genomics, University of Miami; Jeffery Vance, M.D., professor of medicine and director of the division of human genomics, University of Miami; and David Herrmann, M.D., associate professor of neurology and pathology, School of Medicine, University of Rochester.
“This international project establishes Wayne State University’s Department of Neurology as the leading inherited neuropathy program in the U.S. and around the world,” said Dr. Robert Lisak, chair of neurology in the School of Medicine. Under Dr. Shy’s leadership, this consortium will bring us much closer to the development of effective treatments for the various forms of CMT.”