At its March meeting, the CMTA Board of Directors approved a new research project aimed at developing biomarkers for CMT1B to aid in the collection of natural history data critical to clinical trials.
CMT1B is caused by mutations in the gene that codes for myelin protein zero (MPZ), the major protein in the myelin insulation that sheaths the axon. Over, time CMT1B axons degenerate because of the abnormal MPZ in myelin, causing weakness, problems with balance and impaired ability to feel touch.
Multiple therapeutic strategies to treat Schwann cells—the cells that make the myelin—as well as to preserve axons are underway for CMT1B. These therapies include Sephin1—a molecule that has been shown to help some MPZ mutant Schwann cells fold MPZ more efficiently—and protein inhibitors Sarm1 and HDAC6, both of which are designed to minimize axonal degeneration.
Measuring disease progression, or natural history, is necessary and challenging in diseases like CMT that progress slowly, requiring clinical outcome assessments (COA) including neurological examinations, testing of patients’ functional ability to perform tasks and evaluation of patient-reported questionnaires. Natural history data is lacking for CMT1B.
The collection of natural history data for clinical trials requires sensitive biomarkers that can show that a therapy is reaching its target and effecting change within a single year. The newly approved project aims to develop protein biomarkers, such as neurofilament L, which can be identified in blood samples, and RNA biomarkers, which can be identified in skin biopsies and used to detect changes in myelinating Schwann cells using a minimally invasive technique. MRI imaging of patients’ legs will also be used to measure disease progression by way of the accumulation of fat in muscles damaged by neuropathy.
The National Institutes of Health recently funded a project to obtain skin and serum samples from 20 CMT1B patients for biomarker analysis, but the diversity of CMT1B presentations required additional samples. The CMTA’s newly approved project will evaluate 60 patients with CMT1B over two years and recruit patients not only from Dr. Michael Shy’s clinic at the University of Iowa, but also from other sites in the Inherited Neuropathies Consortium, including leading CMT clinics in London, Milan, Rochester, New York and the University of Pennsylvania.
The CMTA recently secured commitments from two families toward the cost of the project.