By Emily Leclerc, Waisman Science Writer
A new test may spur advances in drug discovery for a rare and debilitating neurological disorder. Charcot-Marie-Tooth disease, a rare inherited neurological disorder, affects more than 2.8 million people around the globe. While the condition is not as severe as the related ALS, its range of symptoms – muscle pain, hand tremors, nerve pain, numbness and muscle atrophy in the arms and legs – worsen slowly over time. There is currently no cure or direct treatments for CMT. The treatments available are supportive in that they help relieve symptoms rather than address the condition’s root cause. Because of CMT’s slow progression and the need for long and expensive clinical trials, it is a challenge for pharmaceutical companies to invest in new treatments when they become available. John Svaren, PhD, a professor of comparative biosciences and a Waisman investigator, is working on ways to change that trajectory for CMT research and possible treatments.
“One of the things that is a problem, in terms of a slowly progressive disease, is that drug companies know that they’ll have to do a much longer clinical trial,” says Svaren. “Whereas in a disease like ALS, where people progress very quickly, anything that changes that course will become quite evident quickly. CMT is different.”
Svaren, who has dedicated his research to advancing knowledge on CMT in the hopes of developing interventions and treatments for the disorder, has devised a way to determine a future treatment’s efficacy months before it would affect a patient’s physical symptoms. He turned a feature of the disease into a biomarker for treatment effectiveness.
The most common type of CMT, CMT1A, is caused by the duplication of the gene PMP22. PMP22 is responsible for making an important component of nerve cells, called myelin, found in the peripheral nervous system (PNS). The PNS is comprised of the nerves that exit the brain and spinal cord to innervate muscles and sensory organs. Myelin increases the efficiency of communication between nerve cells and is important for the proper functioning of the brain and the PNS.
Instead of having two copies of PMP22, a person with CMT has three. That extra copy causes an overproduction of the myelin protein produced by the PMP22 gene. A person with CMT makes 50% more of that protein than a person without CMT. Such overproduction causes abnormalities in the myelin, resulting in inefficient communication along the long nerves that connect the spinal cord to muscles. Theoretically, if the amount of the protein being made could be reduced, that reduction could indicate an effective CMT treatment.
Svaren designed a way to more easily and efficiently monitor the PMP22 gene levels in a person. “We devised a way where we could take skin biopsies and, using special techniques, measure the PMP22 gene levels in it,” Svaren says. “The idea is that if a company had a clinical trial, they could use the skin biopsies as an assay within the first month or so to see if the treatment is working.” These skin biopsies could provide researchers an easy way to determine the PMP22 levels in a patient in the initial stages of a clinical trial, effectively providing an early assessment of whether a longer clinical trial will be successful.
When future treatments for CMT make it through the pipeline and become ready for clinical trials, Svaren’s skin biopsy technique will hopefully incentivize drug companies to invest in these trials and bring these drugs to the CMT community. Svaren is continuing to look for more biomarkers that can be used in a similar manner.
“We have been collaborating with a leading CMT neurologist at the University of Iowa, Dr. Michael Shy, to find something you can measure in blood that would be treatment responsive and would precede any clinical improvement,” Svaren says. “Because then you can get intermediate data to justify the continuation of the clinical trial to an endpoint where patients actually begin to really improve.” Having a combination of biomarkers could improve the efficiency of a clinical trial even more.
In addition to investigating CMT biomarkers, Svaren is actively researching the underlying mechanisms behind CMT in the hopes of using that knowledge to develop potent and effective treatments. “We’re involved in efforts to not only stimulate companies to invest in clinical trials but also to try and come up with new cures for CMT,” Svaren says. “As part of our work, we try to provide good science that also recognizes the barriers that exist for companies to invest in CMT.”
His hope is that when a new treatment becomes available, whether it is developed by him or another lab or company, that the clinical trials will be streamlined to create an easy process from the lab bench to the bedside.
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