A Wayne State University physician is seeking a better way to determine the effectiveness of treatments for Charcot-Marie-Tooth disease (CMT), or inherited sensory-motor neuropathy, a disease that afflicts one in 2,500 people.
Sindhu Ramchandren, M.D., assistant professor of neurology in WSU's School of Medicine, believes the current lack of effective treatments for CMT may be because researchers are measuring the wrong outcomes. With a four-year, $661,000 Mentored Career Development Award from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, she is working to develop an outcome measurement that accurately reflects CMT progression in children.
CMT refers to a heterozygous group of diseases caused by mutations in more than 50 genes. One of the most common genetic nerve diseases, it affects more than 120,000 Americans and 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. Some rely on foot or leg braces or other orthopedic devices to maintain mobility.
The identification of disease-causing genes has made the development of rational therapy a possibility in CMT. However, the lack of outcome measures to assess treatment effects in clinical trials is currently limiting therapeutic advances for CMT.
One of the most recent trials spanned several countries and involved ascorbic acid, or vitamin C, after animal models showed dramatic improvement in functioning.
"That gave a lot of hope to a lot of people," Ramchandren said.
One criticism of that group of trials is that they were rushed and used different outcome measures, but she said the rush was necessary because of the concern that CMT patients might medicate themselves with vitamin C in large quantities, and researchers wanted to see if the therapy actually was safe and effective in a randomized trial.
Trials in Australia, France, Italy, England and the Netherlands concluded that ascorbic acid, given as a medication, was safe but ineffective.
"One concern with those trials was that outcome measures varied," Ramchandren said. Some researchers measured a combined outcome score called the Charcot-Marie-Tooth Neuropathy Score, which was developed by Michael Shy, M.D., WSU professor of neurology and Ramchandren's mentor for her current study. Others looked at whether the speed of nerve conduction improved.
Because financial constraints typically limit trials to one or two years, Ramchandren said, an outcome measurement is needed that could change within that time period.
"A good outcome measure will show changes in scores in a short time period so that, when used in a trial, if a drug is effective, we should see those scores improve," she said. "However, if you use an outcome measure that barely budges in a short time period, there's not much chance you will get a dramatic improvement in scores, even if you have a good medication. So, with the recent CMT trials, it may very well be that vitamin C is ineffective, but we can't say for sure when there are doubts about what we are measuring."
With this grant, she will use data from an ongoing consortium study by Shy that collects natural history data on children and adult CMT patients to see how the disease progresses over time. Shy is mentoring Ramchandren as she develops a quality-of-life instrument to measure how CMT impacts children's lives.
Using a questionnaire format, Ramchandren will try to determine what kinds of physical activities CMT restrains. Questions also will address the disease's effects on social roles, such as playing with friends and interaction with families and teachers, as well as emotional behavior, depression and anger.
"We want something that enables children to tell us how this disease impacts their lives at any given point," she said. Questionnaires will be given to all children who come to Wayne State's CMT clinic through the consortium. Scores will be aligned with physical functioning and electrophysiologic studies to spot correlations between how patients feel they are doing and how the disease actually is impacting them neurophysiologically.
"We have shown that quality-of-life scores are low in children with CMT compared to healthy children," Ramchandren said. "We are hoping to show that if those scores change dramatically over the next two to three years, then quality of life might be an outcome measure that can be used in a clinical trial."
Such methodology has worked very well in cancer research, she said, where sometimes quality-of-life scores are first to improve, and then over time researchers see changes in tumor size or disease physiology. Ramchandren believes the same approach could be used for CMT and is working with mentor Lawrence Lum, M.D., professor of oncology at WSU and the Barbara Ann Karmanos Cancer Institute, on early phase clinical trial methodology training. Researchers there take bench work from animal models and translate it into new cancer therapies, she said.
Her eventual goal is to develop a clinical trials unit for all neuromuscular disorders, capable of translating promising animal research into new treatments.
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