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. One recently announced breakthrough came from our partnership with Ionis, which has pioneered development of antisense oligonucleotide (ASO) technology. Rodent studies showed a dramatic improvement in two models of CMT1A, and Ionis is currently working on developing refined versions for testing in clinical trials. Our partnership with Genzyme, a Sanofi company, enabled us to screen their entire compound collection, and we are now testing a leading candidate in a variety of secondary assays and animal models. In addition, the alliance has now expanded to the evaluation of additional molecules that have emerged from other Sanofi programs, and a number of these drug prototypes are being tested as well. Laboratory and animal models of CMT1A have been made available to five additional CMTA alliance partners for testing of therapeutic compounds. Dr. Michael Shy, together with the members of our Clinical Expert Board (CEB), is leading the effort to develop the best outcome measures and biomarkers for clinical trials of CMT1A therapeutics.
This CMT subtype is caused by mutations in the Myelin Protein Zero (MPZ) gene. Scientific Advisory Board members Drs. Michael Shy, Lawrence Wrabetz, and Maurizio D’Antonio are experts in this area. In partnership with InFlectis BioScience, we are engaged in further testing of a novel molecule called Sephin, which has shown dramatic improvement in the S63del mouse model of CMT1B. Also, we now have mouse models of all three major clinical presentations of CMT1B. In the late onset type, we are testing how inhibiting axon degeneration pathways can stabilize motor and sensory neurons, an approach which is the focus of pharmacological development by many of our partner companies. This will be the first test of such pathways in a CMT model, and it is possible that this approach may have broad applicability to other types of CMT.
Until now, there was only one mouse model of CMT1X, but it was not a direct replica of the human mutations in GJB1. Therefore, the CMTA has sponsored the development of four mouse models of CMT1X, one of which has been developed in partnership with Dr. Robert Burgess at the Jackson Laboratory. These models will be used to test therapeutic approaches such as the inhibition of macrophages. Dr. Rudolf Martini at the University of Würzburg, Germany has found that reducing this type inflammation has a very positive effect in a mouse model of CMT1X. In addition, CMT1X also is characterized by degeneration of motor neurons and is therefore an ideal target for the axon degeneration therapies mentioned above for CMT1B. Finally, the work of Dr. Kleopas Kleopa at the Cyprus Institute of Neurology and Genetics has shown the first example of a successful gene therapy in a CMT1X mouse model, and he is continuing these studies toward clinical trials with this novel type of therapy for not only CMT1X but also CMT4. The CMTA convened a workshop with some of the world’s top gene therapy experts to help identify the key steps in translating these findings into human clinical trials for CMT1X. Again this approach can be applied to other types of CMT.
CMT2A is caused by dominant mutations in Mitofusin 2 (MFN2). The STAR team has developed two excellent 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 at Cedars-Sinai Medical Center. As part of its Patients as Partners in Research initiative, the CMTA has sponsored a study with the University of Iowa CMT Clinic and CMTA Center of Excellence to look at pulmonary function for people who have CMT2A. To fund this important study, J.D. and Brenda Griffith made a donation to the CMTA in memory of their daughter Marah. In partnership with several companies, therapeutic approaches under study include inhibition of axon degeneration, as well as the development of gene therapy, which has recently been shown to be successful in another motor neuron disease known as Spinal Muscular Atrophy (SMA). Finally, other candidate molecules have emerged from academic research and animal studies, and planning is underway to test these as well.
CMT2E is caused by dominant mutations in the neurofilament light protein (NEFL) gene. With support from the CMTA, one of the best mouse models of CMT2E, made by Dr. Ronald Liem at Columbia University, has been extensively characterized in collaboration with Dr. Steven Scherer at the University of Pennsylvania. Both human and mouse stem cells containing CMT2E mutations have been differentiated into motor neurons and are being used in drug screens to identify therapies that prevent aggregations of neurofilaments seen in CMT2E.
CMT4C is caused when both versions of an important gene (SH3TC2) required for healthy myelin are deficient. To restore function of these genes, the gene therapy approach described above for CMT1X has also been tried for CMT4C by Dr. Kleopas Kleopa and has shown very positive results. We anticipate this approach 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. The CMTA is helping to identify the genes that cause CMT, and identifying mutations is an important first step in the process. 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.