The CMTA is committed to extending the STAR initiative to other kinds of CMT, such as CMT Type 2. Because CMT2 has diverse genetic causes, and likely multiple disease mechanisms, the CMTA sponsored a workshop in San Diego in November, 2010, and sought to obtain the advice and direction of the most knowledgeable experts in the world. The meeting was attended by more than 30 scientists, and, as a result of the dynamic exchange of ideas, the CMTA has formulated strategies for developing treatments for CMT Types 2A and 2E.
CMT2A is caused by dominant mutations in MFN2. It has been shown that MFN1 can compensate for MFN2 in cell models, and the over-expression of MFN1 can even compensate for the effects of dominant MFN2 mutants. Thus, the goal is to be able to use high-throughput screening (HTS) to identify small molecules that up-regulate the expression of MFN1 in human neuronal cell lines and determine whether they can rescue the effects of dominant MFN2 mutants in cells derived from CMT2A patients and in laboratory models of CMT2A.
Step 1. The CMTA is funding a project by Dr. Stephan Züchner to further refine the development of laboratory models to evaluate the CMT2A pathological process in vivo and provide a tool for pre-clinical testing. In addition to crossing laboratory strains to obtain the best phenotypic model, crossing the MFN2 knock-in model into the existing MFN2 and MFN1 knock-out models could further solidify, in vivo, the hypothesis that MFN1 expression rescues MFN2 mutants. To improve the usefulness and applicability of laboratory models, the CMTA is also pursuing development of another model of CMT2A using some newly available technology, and this model is being evaluated for study of the disease and development of drugs.
Step 2. To enable HTS, the CMTA is funding a project to develop cell-based assays that will detect compounds that increase the level of the MFN1 gene. These assays will be screened using state-of-the-art compound collections at NIH/NCATS (described above). As another testing platform, we are also developing several human stem cell lines derived from CMT2A patients in a collaboration of Dr. Michael Shy with the Induced Pluripotent Stem Cell core at the University of Wisconsin (directed by Dr. John Svaren and Dr. Anita Bhattacharyya). These stem cells will be differentiated into human motor neurons and will constitute another testing platform in the battery of tests that will be used to evaluate candidate drugs for CMT2A.
CMT2E is caused by dominant mutations in NEFL, which prevent the neurofilament light protein from assembling properly and result in the formation of aggregates or abnormal filaments. The goal is to find small molecules that can decrease aggregate formation and/or promote the formation of normal appearing neurofilament. Demonstration of these effects would be identified by rescuing the effects of dominant NEFL mutants in cells derived from CMT2E patients and in animal models of CMT2E. This project is being conducted by Dr. Ron Liem in collaboration with Dr. James Inglese.