MOST RECENT STAR RESEARCH UPDATES
Demyelinating CMT: Type 1, Type X
and Type 4 STAR Research Agenda
Demyelinating forms of CMT affect the protective coating, or myelin, that insulates the “electrical wire” that is the nerve. Research specific to demyelinating forms of CMT includes some two dozen projects.
Axonal CMT: Type 2
STAR Research Agenda
Axonal forms of CMT affect the “electrical wire” that is the nerve, which is surrounded by the protective insulator coating known as myelin. Research specific to axonal CMT includes some two dozen projects.
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. Through STAR, we are screening new drug candidates and exploring gene therapy approaches to treat CMT1A. We recently approved a project that will be spearheaded by Drs. Kleopa, Svaren, and Gray in which they will target CMT1A for gene therapy by testing the distribution of AAV9 in large animal models and testing new AAV variants to optimally reach the Schwann cell.
We are also exploring other gene therapy approaches including gene editing and the use of antisense oligonucleotides (ASO). In December 2017, a breakthrough came from our partnership with Ionis, which has pioneered development of 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 have tested potential candidates in a variety of secondary assays and animal models.In addition, the alliance supported work of additional biomarkers to help prepare for clinical trials in CMT. 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. Laboratory and animal models of CMT1A have been made available to five additional CMTA alliance partners for testing of therapeutic compounds, including the use of drugs to target axon degeneration.
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. Additional drugs aimed at other targets in the same pathway have been developed for other disorders, such as stroke, Alzheimer’s and retinal degeneration, and these are being tested in the CMT1B models mentioned above.
Also, we now have mouse models of all three major clinical presentations of CMT1B. In the late onset type, we are testing (using the T124M mouse model) 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.
In addition, we are exploring other drugs that modulate the UPR in the lab of Maurizio D’Antonio, where we have approved a project to look at other UPR modulating compounds developed at Scripps Institute.
To spur development of novel therapies for CMT1X, the CMTA has sponsored the development of four new mouse models of CMT1X, two of which have been developed in partnership with Dr. Robert Burgess at Jackson Laboratories.
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 other demyelinating forms of CMT (CMT1A and CMT4C). 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, and we are following a strategic plan developed from this meeting.
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, as recently announced by Passage Bio. Gene Therapy approaches which have recently been shown to be successful in another motor neuron disease known as Spinal Muscular Atrophy (SMA). Finally, other candidate molecules have emerged from progress in understanding mitofusin activity, and planning is underway to test these as well.
CMT2E is caused by dominant mutations in the neurofilament light protein (NEFL) gene. Mutations in NEFL cause CMT2E. 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. In addition, we are exploring several therapeutic approaches for treating CMT2E, including gene editing, and the use of small molecules including HDAC 6 inhibitors and drugs that target axon degeneration pathways (both mentioned above in CMT1B and CMT2A).
CMT4C 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 has also shown success in studies conducted by SAB member Dr. Kleopa in a mouse model of CMT4C. Synergistic research efforts in CMT1A and CMT1X are being used to optimize delivery of gene therapy to Schwann cells.
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 by supporting work led by Dr. Stephan Züchner of the University of Miami. Identifying mutations is an important first step in the process. Even for rarer types of CMT, some of the advances in the eventual treatment of axon degeneration may be applicable as these therapies are developed. 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.