CMT1X
CMT1X is the second most common form of CMT, accounting for 10-16 percent of all cases. The gene that causes CMT1X is GJB1 and the protein is called connexin 32. 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 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 being developed 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.
Below we share with you the research projects the CMTA is currently funding for 1X as well as a description of the remarkable STAR Biotech Alliance Partners with whom we collaborate to advance research for CMT.
View the projects currently active or recently completed in the CMT1X drug development pipeline.
PROJECT GOAL: A TRANSLATABLE GENE THERAPY FOR CMT1X
Grant Amount: $138,215
Principal Investigator: Kleopas Kleopa, MD, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
The Charcot-Marie-Tooth Association (CMTA) and the Muscular Dystrophy Association (MDA) have jointly awarded a research grant totaling $276,430 over three years to Kleopas Kleopa, MD, professor and senior consulting neurologist at the Cyprus Institute of Neurology and Genetics. Dr. Kleopa is a world-renowned expert on gene replacement therapy for CMT1X, the second-most-common form of CMT).
Mutations in the gene coding for the gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), are associated with the X-linked form of CMT (CMT1X), which affects approximately 1 in 25,000 people. Using this grant funding, Dr. Kleopa will perform critical, proof-of-concept studies to test whether delivery of the Cx32 gene using an adeno-associated virus (AAV) vector can improve symptoms in a mouse model of CMT1X as well as determine the optimal route for delivery of the therapy.
The project will test several types of AAV and different injection paradigms to determine the best method to restore the function of Cx32 in Schwann cells. Positive results may help advance development of treatments for other types of CMT affecting Schwann cells, as a similar AAV approach can be applied to CMT1A and other subtypes of CMT1.
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: DETERMINE WHETHER SARM1 IS A THERAPEUTIC TARGET IN CMTX
Grant Amount: $120,544
Principal Investigator: Steven Scherer, MD, PhD, University of Pennsylvania
Dr. Scherer will conduct tests to determine whether inhibiting SARM1 is of therapeutic benefit in CMTX.
PROJECT GOAL: INHIBITION OF SARM1 IN CMT TYPES 1A, 1X, 2E, 2D AND 2S
Grant Amount: $110,000
Principal Investigator: Robert Burgess, PhD, The Jackson Laboratory
Dr. Burgess will conduct tests to determine whether inhibiting SARM1 is of therapeutic benefit in multiple forms of CMT.
PROJECT GOAL: DEVELOP CMT1X BIOMARKERS FOR CLINICAL TRIAL READINESS
Grant Amount: $601,407
Principal Investigators: Michael Shy, MD, University of Iowa; John Svaren, PhD, University of Wisconsin
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 CMT1X and develop and characterize biomarkers for CMT1X.
PROJECT GOAL: PRODUCTION AND CHARACTERIZATION OF NEW MODELS OF CMT1X
Grant Amount: $150,932
Principal Investigators: Charles Abrams, MD, PhD, University of Illinois at Chicago; Steven Scherer, MD, PhD, University of Pennsylvania
Drs. Abrams and Scherer will produce a mouse model with characterizations of CMT1X.
PROJECT GOAL: PRODUCTION AND CHARACTERIZATION OF NEW MODELS OF CMT1X
Grant funded through the National Institutes of Health
Principal Investigator: Robert Burgess, PhD, The Jackson Laboratory
In a research partnership with the National Institutes of Health (NIH), Dr. Burgess will produce a mouse model with characterizations of CMT1X.
PROJECT GOAL: TREAT CMT1X MOUSE WITH COMMON FOOD ADDITIVE TO PREVENT METABOLIC STARVATION
Grant Amount: $100,000
Principal Investigators: John Svaren, PhD, University of Wisconsin; Robert Burgess, PhD, The Jackson Laboratory
CMT1X is a demyelinating CMT and it affects roughly 15 percent of all cases. It is caused by mutations in gap junctions which form channels that allow transport of metabolic substances across the many layers of myelin.
Recent studies have highlighted the important role of metabolic exchange between the axons of nerves and the myelin sheath made by Schwann cells, and the lack of functional channels could be the key factor that drives the deterioration of axons in this type of CMT.
Therefore, this grant will test whether a commonly used food additive can be used to prevent metabolic starvation and maintain healthy nerves when channels are blocked by the mutations that cause CMT1X. The food additive has been proven to be safe at even high doses in preclinical/clinical studies.
Svaren and investigators at The Jackson Laboratory will use a mouse model of CMT1X to perform the studies, which will take about a year. If successful in demonstrating proof of the concept, these studies could lead to an accelerated path to clinic, getting the therapy to patients on a faster track.
Acceleron Pharma
Acceleron Pharma, a Cambridge, MA based biopharmaceutical company dedicated to developing medicines to treat serious and rare diseases, developed ACE-083, a therapeutic candidate designed to affect muscles to maximize growth and strength. Acceleron initially developed ACE-083 for disorders such as CMT and FSHD (Facioscapulohumeral Muscular Dystrophy). After Phase 2 Trials in both CMT and FSHD, Acceleron concluded studies.
Read about the Patients as Partners in Research Initiative ⟶