2015 STAR Research Update
STAR Research Updates by Type
CMT1A is caused by the duplication of the Peripheral Myelin Protein 22 (PMP22) gene, which leads to the demyelination of the peripheral nerves. Our partnership with Genzyme, a Sanofi company, resulted in screening their entire compound collection (almost 2 million compounds) and has identified some candidate compound series for treating CMT1A, which are being tested in a variety of secondary assays and animal models. In addition, both laboratory and animal models of CMT1A have been made available to additional CMTA alliance partners for testing of therapeutic compounds, and we hope to be able to share some of these promising data in the very near future. These models include a human stem cell model of CMT1A, made in collaboration with the NYSCF, which in addition to therapeutics testing, is being made available to the research community. Dr. Michael Shy is leading efforts, together with the members of our Clinical Expert Board (CEB), to develop the best outcome measures for clinical trials of CMT1A therapeutics.
This CMT subtype is caused by mutations in Myelin Protein Zero (MPZ). Board members Dr. Michael Shy and Dr. Lawrence Wrabetz are collaborating with Dr. James Inglese at NIH to explore the unfolded protein response pathway, which plays a causative role in CMT1B. Studies of this pathway have yielded some candidate compounds for treatment, which have been shown to be effective in one model of CMT1B. We are developing studies to see if this approach will treat the three major clinical presentations of CMT1B. Another approach in development is to inhibit the immune response to the nerve damage that occurs in CMT1B.
Dr. Rudolph Martini at the University of Würzburg, Germany, has found that inhibiting the macrophages associated with inflammation has a very positive effect in a mouse model of CMT1X, which is caused by mutation of the GJB1 gene. Based on his studies, we are developing approaches to inhibit macrophages as a clinical treatment. In addition, the work of Dr. Kleopas Kleopa has shown the first example of a successful gene therapy in a CMT1X mouse model, and he is continuing these studies to optimize this novel type of therapy for not only CMT1X but also CMT4.
CMT2A is caused by dominant mutations in Mitofusin 2 (MFN2). The STAR team has developed two good rat models for CMT2A, which are being made available to the research community and represent an important tool to test potential new modulators of mitofusin activity. Stem cell models of CMT2A have also been developed for CMTA-sponsored research in the laboratory of Dr. Robert Baloh, Cedars-Sinai Medical Center.
CMT2E is caused by dominant mutations in the neurofilament light protein (NEFL) gene. Mutations in NEFL cause CMT2E but other mutations in the same gene are associated with ALS, suggesting there may be a connection between them. One of the best mouse models of CMT2E, made by Dr. Ron Liem at Columbia University, has been extensively characterized by the CMTA and now represents an important model for therapeutics testing. Stem cells containing CMT2E mutations have been differentiated into motor neurons and used to create a test for therapies that prevent aggregations of neurofilaments seen in CMT2E.
CMT4 is caused when both versions of an important gene required for healthy myelin (SH3TC2) are deficient. To restore function of these genes, the gene therapy approach described above for CMT1X is also being tried for CMT4C by Dr. Kleopa. If successful, these studies may highlight a novel approach that will be applicable to other forms of CMT4.
Unidentified Types of CMT
Every year more types of CMT are identified by STAR researchers, but there are many left to discover. Identifying mutations is an important first step in the process. The CMTA is helping to identify the mutation and type of CMT that little Julianna Snow had so we can put a STAR project in place to work toward a treatment for her father and other people affected by it. If your type is not yet identified, please visit a CMTA Center of Excellence to share your DNA with our STAR database to accelerate the pace of discovery.
If you haven’t had genetic testing to learn what type of CMT you have, please visit the genetic testing page to learn more.