CMT2A

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 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.

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.

2021 CMT2A RESEARCH PROJECTS

CMT2A Pipeline
PROJECT GOAL: THERAPEUTIC INACTIVATION OF CMT2 DISEASE ALLELES WITH CRISPR
Grant Amount: $664,261
Principal Investigators: Luke Judge, MD, PhD, University of California-San Francisco; Bruce Conklin, MD, University of California-San Francisco
Drs. Conklin and Judge

Drs. Judge and Conklin will optimize allele-specific CRISPR inactivation of dominant CMT2 mutations in vitro and determine whether in vivo delivery of disease-specific CRISPR reagents can prevent disease pathology in a rodent model of CMT2A.

PROJECT GOAL: EARLY PHASE TREATMENT TRIALS OF CMT2A
Grant Amount: $18,942
Principal Investigator: Michael Shy, MD, University of Iowa
Dr. Michael Shy

Dr. Shy will determine the extent of respiratory compromise in individuals with CMT2A and determine the tolerability and potential use of NIPPV in individuals with CMT2A to improve respiratory function.

PROJECT GOAL: DEVELOP CMT2A BIOMARKERS FOR CLINICAL TRIAL READINESS
Grant Amount: $601,407
Principal Investigators: Michael Shy, MD, University of Iowa; John Svaren, PhD, University of Wisconsin
Drs. Svaren and Shy

In order to prepare for clinical trials for CMT, there is ongoing work to develop more sensitive outcome measures, and there is a need for complementary biomarkers, particularly target engagement measures that can be used in clinical trials for candidate therapies. Drs. Shy and Svaren will characterize CMT outcome measures in cross sectional and longitudinal studies of 60 subjects with CMT2A and develop and characterize biomarkers for CMT2A.

PROJECT GOAL: CREATE AND CHARACTERIZE A CMT2A RAT MODEL
Principal Investigator: Steven Scherer, MD, PhD, University of Pennsylvania
Dr. Steven Scherer

The CMTA has established a unique capability to develop new therapies directly with companies and research labs, and to expertly test those potential therapy candidates. This allows a company or research lab 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 supported the creation and characterization of a best-in-class rat model of CMT2A so we know when to test a drug or gene therapy, for how long and what signifiers of improvement need to be measured. We currently have six other animal models available and work with expert contract research organizations to engage 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.

CMT2A BIOTECH ALLIANCE PARTNERS

PASSAGE BIO & UNIVERSITY OF PENNSYLVANIA

Passage Bio, a genetic medicines company developing AAV-delivered gene therapies for the treatment of rare monogenic central nervous system (CNS) diseases has licensed a sixth gene therapy development program under its research, collaboration and license agreement with the University of Pennsylvania and its Gene Therapy Program (GTP). The license is for the clinical development of a potential treatment for patients with Charcot-Marie-Tooth Neuropathy Type 2A (CMT2A).

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 CMT2A. These cell lines give companies the ability to test therapies on patients’ own genes, the first step to enabling a personalized medicine strategy.

PSYCHOGENICS; CLEVELAND CLINIC; CHARLES RIVER

The 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 animal models of CMT2A 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.

REGENACY PHARMACEUTICALS

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 E

Confidential Partner E has a drug candidate shown by them to have efficacy in an ALS animal model. To explore its possible use in CMT they have licensed a human CMT2A stem cell line to develop an understanding of whether the known mechanism of action of the drug can translate to a positive effect in CMT, using a human test system. Confidential Partner A owns a drug candidate that was 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 and Type 2 CMT animal models. We have some evidence of effect in these models, and detailed data on which nerves are affected was passed to the company to complete the collaborative studies. They have chosen, however, to relinquish their option on the drug candidate as the data was not sufficiently compelling as to drive a clinical development decision.

Confidential Partner F

Confidential Partner F is developing a novel biological approach to treat CMT and asked for our help in evaluating their drug candidate in our CMT2A rat models. This drug candidate is already in drug treatment trials in patients for another disease indication. These studies have shown effects in one of the outcome measures employed, and they have recently extended the study to collect additional data to establish if peripheral nerves are being protected.

STAR Confidential Partner G

Confidential Partner G is a company built around a highly novel system to screen drugs that have a known mechanism of drug targeting for their ability to affect a disease “signature”. Their focus is on using human and animal disease models systems for this work that are highly representative of a disease. They have licensed a human CMT2A stem cell line from us for use in these studies, in which they turn the stem cells into motor neurons in a dish. Several potential targets were identified by them, and agents which can regulate the activity of these targets were tested in the cell lines to determine effect. They initially reported success and discussed advancement to animal model testing with us. However, recently they reported they have been unable to validate these studies, and currently are internally discussing approaches to advance a CMT effort.

CMTA-STAR OVERVIEW AND RESEARCH UPDATE

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.

STAR Update for Axonal CMT

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