April 11, 2019 — The Charcot-Marie Tooth Association today announced $1 million in research grants to industry partners and top CMT scientists worldwide, bringing to more than 50 the number of active research projects currently being funded. Every grant will have an impact on therapy development, from improving understanding of disease mechanisms to discovering new therapeutic targets and moving these into clinical trials. The grants represent the CMTA’s commitment to finding treatments and a cure for the CMT community and cover work on CMT types 1, 2, and 4.

Type 1 Gene Therapy Project:

Kleopas A. Kleopa, MD, is receiving funding for a gene therapy project at the Cyprus Institute of Neurology. The results of this study could have implications for all Type 1’s.
The CMTA and the Muscular Dystrophy Association awarded Dr. Kleopa Kleopas of the Cyprus Institute of Neurology and Genetics $276,000 to test AAV (adeno-associated virus) delivery of the GJB1 gene to stop CMT1X. Many CMT1X cases are thought to be caused by loss of function of the connexin 32 protein encoded by the GJB1 gene. Dr. Kleopas will perform critical, proof-of-concept studies testing whether AAV delivery of the GJB1 gene can ameliorate disease in mouse models of CMT and whether it’s the optimal route for delivering the therapy. The project will employ several types of AAV to optimize Schwann cell infection. The work improves upon the lentiviral approach employed earlier for CMT1X. The results of this study could have implications for all Type 1’s.

Type 1B Project:

Dr. Maurizio D’Antonio of the San Raffaele Scientific Institute received $104,000 to verify if compounds that activate the Ire1a-mediated Xbp1 splicing can improve myelination in CMT1B dorsal-root-ganglia (DRG) explants. Dr. D’Antonio will also explore the role of ATF6a in neuropathy and test molecules able to modulate the ATF6a pathway in myelinating DRG explants from CMT1B mice.-While the Sephin1 drug has shown great promise in treating CMT1B mouse models, additional candidate drugs are being developed that also modulate related pathways Xbp1 and ATF6a.The targeting of these stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with several CMT neuropathies.

Type 4 Gene Therapy Project:

Dr. Kleopas Kleopa also received $120,000 to develop a clinically translatable gene therapy to treat CMT4C, a demyelinating neuropathy caused by autosomal recessive mutations in the SH3TC2 gene. expressed specifically in myelinating Schwann cells. Kleopa recently showed that a lentiviral gene delivered by intrathecal injection can provide a partial therapeutic benefit in a CMT4C model. In this project, Kleopa will explore the possibility of delivering the therapeutic SH3TC2 gene by a clinically translatable AAV9 vector. He will test this gene therapy approach in the Sh3tc2-/-mouse model of CMT4C at early and late stages of the neuropathy. This study will provide the proof of principle for clinical translation of CMT4C gene therapy. For this exciting research project, the CMTA is inviting ALL CMT4C patients and families to stand with us and get involved. To learn more, please email info@cmtausa.org.

Axonal Degeneration Study:

The CMTA awarded Dr. Steven Scherer at the University of Pennsylvania $120,000 to determine whether axonal loss in the 1X mouse model (Gjb1 mice) can be ameliorated by crossing it with a SARM1-null, which has been shown in numerous studies to reduce the organic compounds called NAD that cause axonal degeneration. Axonal loss is a major driver of CMT progression. An enzyme called SARM1 breaks down NAD, leaving axons unprotected and susceptible to degeneration. It is important to determine if SARM1 antagonists, which are substances that interfere with or prevent the action of another, can serve to protect against axonal degeneration.

Clinical Trial Readiness Projects:

Dr. Michael Shy, principal investigator for the Inherited Neuropathies Consortium (INC) received $206,000 to support the INC’s efforts to find treatments for people who have inherited neuropathies. Since 2008, members of the INC have identified many new mutations in genes that cause CMT, discovered new genes that cause CMT, illuminated the molecular pathogenesis of many disorders including an effective therapy for a CMT-related disease, performed translational studies with animal models of CMT that may lead to new therapies, developed management strategies and standards of care for people with CMT, published strategies for genetic testing for inherited neuropathies, developed biomarkers, participated in three clinical trials of ascorbic acid for CMT1A, and developed Clinical Observation Assessments that have enabled natural history studies and will facilitate clinical trials. INC members have enrolled more than 10,200 participants, examined more than 5,300 individuals with CMT, and published more than 250 manuscripts based on INC data. Achieving trial readiness is now the most important unmet need for CMT and the INC’s main goal in the upcoming CMTA cycle. Learn more about how you can be one of our CMTA Patients as Partners in Research and participate in natural history and other studies that will help us prepare for clinical trials. Drs. Kate Eichinger and David Herrmann of the University of Rochester Medical Center received $109,000 to examine the reliability, validity and responsiveness of wearable sensors in individuals with CMT 1A. As more and more research projects approach the clinical trial phase, studies are urgently needed to identify valid and responsive outcome measures. Recently, a study successfully used anti-sense oligonucleotides to knock down peripheral myelin protein 22KDa (PMP22), substantially reversing the phenotype of the rat and C22 mouse models of CMT1A, including measures of strength and balance (hind limb, grip strength and time on the rotating rod). The ability to measure changes in strength, motor function and balance over short periods of time in early phase human trials is essential to identifying potential therapeutic agents. This study will provide initial data regarding sensor-derived parameters, which is necessary to plan a larger multisite study to develop this outcome measure for future clinical trials. Dr. Michael Shy’s lab at the University of Iowa received a $50,000 follow-up grant to continue work on the biomarkers needed to measure progress in clinical trials to determine if subtype-specific biomarkers can be used to complement the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and MRI measures in assessing the disease status of the most common forms of CMT–1A, 1B, 1X. and 2A. To date, Dr. Shy’s research team has generated a considerable amount of promising data, but more time is required to accrue sufficient samples from rarer CMT subtypes. Funding will support work to expand our ability to detect successful outcomes in clinical trials, not only for CMT1A, but also other CMT subtypes. Sample collection will be coordinated with MRI studies being conducted by INC.

Research Tools to Test Drugs and Potential Therapies:

The CMTA also recently approved an $87,000 grant for a one-year project to build out research tools for 1X by fully characterizing the connexin32 deletion mouse. The CMTA’s STAR strategy has been extremely successful in creating partnerships with pharmaceutical companies by providing access to our “toolbox” of animal models, cell lines and assays. We have funded five similar projects to support the buildout of our 1A, 2A and 2E animal models. This was accomplished through pooled efforts among animal breeders and behavioral, electrophysiological and histological testing. Animal models exist for 1X, but full characterization is needed. When completed, this animal profiling will bring type X current with our alliance strategy needs.

Strategic Partnerships:

The CMTA’s Board of Directors also recently approved over $200,000 in research projects to support the organization’s strategic partnerships with pharmaceutical and biotechnology companies to develop treatments for the community. Stay tuned for more updates from the CMTA on progress from this round of research grants and awards.