Since 2008, the CMTA-STAR has made historic progress in developing a treatment for CMT1A. The chart above shows the major milestones we have reached, and the chart below shows projects currently active or recently completed in the CMT1A drug development pipeline. (Click images to enlarge.)
CMT1A is the single most common form of Charcot-Marie-Tooth disease. This sub-type of CMT is caused by the duplication of the Peripheral Myelin Protein 22 (PMP22) gene, which leads to the demyelination of the peripheral nerves.
Through the CMTA-STAR multi-pronged approach to research, we are screening new drug candidates and exploring gene therapy strategies to treat CMT1A, including gene editing and the use of antisense oligonucleotides (ASOs).
Laboratory and animal models of CMT1A are an essential resource in this process, and we are continuing to develop and make them available to CMTA-STAR alliance partners for testing of therapeutic compounds.
Clinical trial readiness is also extremely important at this stage in the development of therapeutics to treat CMT1A, and Dr. Michael Shy, together with the members of our Clinical Expert Board (CEB) and our CMTA-STAR alliance partners, is leading the effort to develop the best outcome measures and biomarkers for clinical trials.
Below we share with you the 2021 research projects the CMTA is currently funding as well as a description of the remarkable STAR Biotech Alliance Partners with whom we collaborate to advance research for CMT.
This work of developing therapeutics for CMT1A requires major funding by the CMTA, so we are extremely grateful to Seth and Missy Warfield for creating the CMT1A Challenge Match. In their push to raise $1 Million for CMT1A research by the end of this year, they will match all donations to their challenge up to $500,000.
PROJECT GOAL: IMPROVE THE PROTEASOME FUNCTION TO TREAT CMT1A
Grant Amount: $204,785
Principal Investigators: Laura Feltri, PhD, University at Buffalo; Lawrence Wrabetz, MD, University at Buffalo; Jordan VerPlank, PhD, University at Buffalo
Previous work has shown that that the accumulation of mutant myelin protein zero protein in CMT1B causes an unfolded protein response (UPR) which leads to the onset of symptoms of the disease. While other approaches to resolve the UPR are in testing (and clinical trials for CMT1A), the Feltri/Wrabetz laboratory has developed a strategy to eliminate the mutant protein by activating the proteasome function.
Approved drugs that have been developed for hypertension and erectile dysfunction are available for testing this strategy. Based on positive results obtained in a short pilot trial in a CMT1B mouse model, this research project will test two other drugs with more optimal pharmacology. Dr. Feltri will use short term studies of the two drugs to establish optimal dosing, and then she will perform a longer efficacy trial. This approach will also be tested in a CMT1A model in parallel to see if these approved drugs could have some benefit for CMT1A.
PROJECT GOAL: ENGINEER/TEST PROMOTERS TO CONTROL EXPRESSION OF THE TARGET GENE BEING DELIVERED TO SCHWANN CELLS BY AN AAV VIRUS
Grant Amount: $154,000
Principal Investigators: John Svaren, PhD, University of Wisconsin; Kleopas Kleopa, MD, Cyprus Institute of Neurology & Genetics,
Nicosia, Cyprus; Steven Gray, PhD, University of Texas Southwestern Medical Center
In order to optimize gene therapy approaches for the Type 1 demyelinating CMT neuropathies, there are important challenges to be overcome which include 1) The development of safe viral vectors (the gene “package” delivered by a virus to cells) and 2) the identification of viruses that can deliver a vector to peripheral nerve and enter Schwann cells with high efficiency.
The proposed experiments will seek to enable a translatable gene therapy approach for CMT1A, CMT1X, and various CMT4 forms. This will also be the first testing of AAV9 virus distribution to Schwann cells in a larger animal model (primate).
PROJECT GOAL: LOWER THE EXPRESSION OF PMP22 GENE
Grant Amount: $60,000
Principal Investigator: John Svaren, PhD, University of Wisconsin
Dr. Svaren will explore approaches in lowering the expression of the PMP22 gene, which is overexpressed in CMT1A patients, by conducting preclinical studies in CMT1A animal models.
In the CMT1A animal models, Dr. Svaren will use an FDA approved drug and similar compounds to test the effectiveness of lowering the expression of PMP22. If successful, this project could lead to an accelerated treatment for patients.
PROJECT GOAL: 1A/1B TARGET VALIDATION
Grant Amount: $88,889
Principal Investigator: Luigi Puglielli, MD, PhD, University of Wisconsin
Dr. Puglielli will conduct genetic, cellular and pharmacologic tests to validate this target. His goal is to determine whether ATase inhibition can rescue the CMT-associated phenotype and to determine the specific translational role of ATase1 and ATase2.
PROJECT GOAL: TESTING HDAC6 INHIBITORS
Grant Amount: $44,507
Principal Investigator: Robert Burgess, PhD, The Jackson Laboratory
Dr. Robert Burgess, a member of the CMTA’s Scientific Advisory Board, is using mouse models of several forms of CMT to determine which types may be candidates for treatment with HDAC6 inhibitors and whether HDAC6 inhibitors may be of therapeutic benefit across a variety of CMT types.
PROJECT GOAL: INHIBITION OF SARM1 IN 1A, 1X, 2E, 2D, 2S
Grant Amount: $110,000
Principal Investigator: Robert Burgess, PhD, The Jackson Laboratory
Dr. Robert Burgess will conduct tests to determine whether inhibiting SARM1 is of therapeutic benefit in multiple forms of CMT.
Sanofi was our first alliance partner for CMT1A and in 2020 evaluated small molecules that came from this joint program as potential new alliance partners have expressed interest in acquiring them. In addition, Sanofi has asked the CMTA to lead testing of a new small-molecule approach that has been advancing for a different but related disease area. In 2020 Sanofi restructured their organization, with closure of their neuroscience unit in Boston.
Ionis was the first partner to demonstrate that a genetic modifier of the PMP22 gene (anti-sense oligonucleotides or ASOs) could effectively repair CMT1A defects in animal models of the disease. Since then, Ionis has been working to solve a generally understood limitation of its technology—the delivery of the ASO to the target Schwann cells. They have acquired from us CMT1A stem cell lines in the NYSCF repository for use in testing different approaches to enhance ASO delivery. We are awaiting results from this work, which would allow their CMT1A effort to advance if successful.
Regenacy owns a drug candidate that has been in human testing for a different disease but may have value in treating CMT. Regenacy accessed our testing resource to evaluate the candidate in several CMT types, including CMT1A. The results of the evaluations were mixed, and Regenacy is evaluating which efforts merit further study via an external collaboration to test activity in cell-based models of CMT.
Confidential Partner A
Confidential Partner A owns a drug candidate derived from a program at a major pharmaceutical company. Based on known evidence of the drug target’s possible role in CMT disorders, the company pursued evaluation in both Type 1 (CMT1A) and Type 2 CMT animal models. We provided partial evidence of effect in CMT1A, and very detailed data that the drug’s effect was primarily on sensory, not motor, nerves. From this data the company concluded that the benefit of using this drug class in CMT therapy was not sufficiently compelling and the effort was ended.
Confidential Partner B
Confidential Partner B, our first alliance partner in this area has been evaluating the delivery of its gene modifying system, packaged inside an AAV virus, to nerves in CMT1A animals. The testing resource is “therapy agnostic” and can be used to evaluate gene therapy approaches as well as ASOs, biologicals and small molecules. The gene localization studies are still in progress, and if delivery is sufficiently effective, this will be followed in 2021 by a complete series of preclinical efficacy studies to determine if the approach can correct the CMT1A defect and restore normal function in the animals.
Confidential Partner C
Confidential Partner C is developing a novel biological approach to treat CMT and asked for our help in evaluating their candidate in both Type 1 (CMT1A) and Type 2 models. These studies showed promising results in both models, and together we are pursuing studies to determine the site of action of the candidate therapeutic, which may not be directly in the nerve but at the junction of nerve and muscle. Additional studies are being discussed that would examine further biomarker elevation in both models and assess the survival of peripheral nerve in the completed studies.
InFlectis BioScience, a French startup company, is working to develop a new approach to CMT1B and CMT1A. Sponsored research studies have been performed in the CMTA-STAR consortium to assess drug effects in both animal models and InFlectis is currently raising funds for clinical trial testing of the molecule in patients.
Pharnext, a French company, is developing a combination of several known drugs for the treatment of CMT1A, which when given together may be effective at slowing progression of the disease. The small molecule combination showed benefit in early clinical trials, and regulatory authorities have asked the company for an additional, expanded trial using the highest proposed dose combination. The company has raised additional funds for this clinical trial extension, and is currently continuing to dose patients. Results are expected in 2Q21.
New York Stem Cell Foundation
In addition to the validated CMT animal models, the CMTA and the New York Stem Cell Foundation (NYSCF) have put together a collection of patient-derived stem cell lines for CMTs, including CMT1A. These cell lines give companies the ability to test therapies on patients’ own genes, the first step to enabling a personalized medicine strategy.
Academic Medical Center, Amsterdam, Netherlands; Max Planck Institute, Göttingen, Germany; Psychogenics; Cleveland Clinic; Charles RiverThe CMTA has established a unique capability to develop new therapies directly with companies and to expertly test those potential therapy candidates. This allows a company interested in positioning a therapy for CMT to access the infrastructure needed to evaluate the therapy without committing significant time and money up front. The CMTA has acquired and characterized best-in-class mouse and rat models of CMT1A so we know when to test a drug, for how long and what signifiers of improvement need to be measured. Currently, six models are well characterized and available, representing four different types of CMT. Expert contract research organizations have been engaged to perform the testing under CMTA direction and our agreement structure lowers common barriers to entry such as confidentiality, retention of intellectual property and long-term financial commitment.
This is an in-depth STAR research update led by CMTA Board Chair Gilles Bouchard and accompanied by CMT scientists and researchers Drs. Svaren, Kleopa, Scherer and Züchner. They share a detailed presentation about the CMTA’s STAR research program and provide updates on the studies being done on CMT by type.