Charcot-Marie-Tooth disease CMTA STAR Program Medical research

Research Progress on Charcot-Marie-Tooth Disease

CMT shark logo

As some of you know, I have CMT, a hereditary disease that I’ve traced back at least five generations in my father’s maternal line. There’s a lot of research being conducted into the 80+ genetic causes of this neuromuscular disorder, much of it sponsored by the CMT Association’s STAR program (Strategy to Accelerate Research.) The various research projects are funded largely by donations from individuals and families who know firsthand what it’s like to live with the debilitating effects of CMT. I recently received an update about research progress, which I’d like to share with you all today.

First, here are some enlightening statistics taken from Wikipedia.

“Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA), is a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, and affects approximately 1 in 2,500 people[1][2] equating to approximately 26,000 people in the United Kingdom and 128,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy.“

More from the Mayo Clinic:

Charcot-Marie-Tooth disease is a group of related conditions all caused by inherited mutations in genes involved with the structure and function of the nerves that serve your feet, legs, hands and arms.

In some cases, these genetic mutations result in damage to the nerve itself. Other mutations damage the myelin sheath, the protective coating that surrounds the nerve. The end result, however, is the same — weaker messages traveling between your extremities and your brain.

Now here is the 3rd Quarter Research Update through September 31, 2015 from CMTA’s CEO, Patrick Livney. (technical but enlightening)

CMT1A (most common form, believed to be the culprit in about 60% of CMT cases)

· Sanofi-Genzyme completed 1.9 million compound screen early in the year. Further work distilled the results down to 742 active compounds. Continuous triage will bring this number down even further over the next quarter. Pilot sets of compounds are being tested using stem cell-derived human Schwann cells (G. Lee, Johns Hopkins), myelination assays in culture (L. Feltri, Univ. of Buffalo), and in primary Schwann cells.

· We initiated a collaborative development of serum biomarkers for CMT1A together with Genzyme. Serum samples are being collected at the University of Iowa. Joint meeting with Genzyme is being planned for November.

· An Addex compound that regulates a target implicated in Schwann cell myelination is being evaluated in studies in CMT1A rodent models.

· An agreement with licensing rights was completed with Affectis Pharmaceuticals to work on a compound that regulates P2X7, a cell surface target on Schwann cells that may regulate myelin formation. This has entered testing in CMT1A rodent models.

· Signed an MTA (Material Transfer Agreement) with AbbVie for use and data on their P2X7-directed compounds.

· The Amgen proteasome inhibitor is currently in testing in rodent models of CMT1A.

· On-going discussion with ISIS to use their custom molecules in an in vivo study. Study has been initiated in a rodent model of CMT1A and samples are being analyzed.

· NCATS (National Center for Advancing Translational Science) has completed a 400,000 compound screen. Svaren laboratory finished a new assay to establish specificity for PMP22 lowering (intended goal) vs. MPZ or Myelin Protein Zero lowering (which would be a negative side effect). Trish Dranchak at NIH has tested and validated this assay. This assay has been used on approximately 10,000 cherry- picked compounds from NCATS screen to identify specific inhibitors of PMP22 expression that do not affect the vital MPZ myelin component. The secondary screen is now completed and under analysis.

· Pfizer provided an additional ~250 compounds from their chemogenomics library that had shown promise of reducing PMP22. These compounds were tested in both PMP22 and MPZ assays listed above. Screen was completed, and we are awaiting Pfizer’s “decoding” of the results.


· Creation of a CMT2A target discovery and drug screening assay has been completed and validated by Brittany Wright (NCATS). It is now ready for pilot screening.

· The next phase of CMT2A projects is being developed:

o Characterization of two mutant rats (H361Y and R364W) by behavioral, electrophysiological and pathological studies, to be done by PsychoGenics and Dr. Steve Scherer in collaboration with Renovo.


· Dr. Liem has demonstrated under a microscope that there are neurofilament clumps evident in the CMT2E mutated mouse that are not evident in the normal or wild-type mouse. He has also shown this in neurons derived from the mouse embryonic stem cells from this model, which has enabled at least limited testing of small compound libraries at Columbia University.

· Mouse colony for CMT2E has been established at PsychoGenics, and phenotyping results (observable traits or characteristics) indicate measurable deficits. Dr. Steve Scherer has also written a proposal to characterize when the mutant mice develop neuropathy, by electrophysiological and pathological studies.

· A number of investigators with experience in disorders related to CMT2E gathered in Chicago for a one-day meeting. A number of relevant results were presented and several initiatives for future efforts for CMT2E were proposed.

CMT 1X (the type that runs in my family)

· Dr. Martini, in collaboration with Plexxikon Pharmaceuticals, has completed a study with an anti-inflammatory compound on a CMT X animal model. His published studies indicate that this approach has positive results in both CMT1X and CMT1B.

· Dr. Scherer has put forth a proposal from Dr. Brett Morrison, which is being reviewed by the STAR Advisory Board (both Science Experts Board and Translational Experts Board)


· Dr. Brittany Wright, in collaboration w/ Dr. Shy’s lab, has built three cell lines associated with the activation of UPR (Unfolded Protein Response), which is believed to be the cause of this disease state. Assays being worked on currently to detect such activation.

· Dr. Wrabetz on track in building CMT1B mutated mouse model.


· Dr. Scheideler and STAR team have considered several presentations made by investigators across the various type 4s. Looking for commonalities and proposals on translational projects to fund. Working on putting together CMT Type 4 STAR team.

· Dr. Kleopa has put together a proposal for CMT4, which is being reviewed by the STAR Advisory Board (both Science Experts Board and Translational Experts Board).


· Dr. Shy sent 18 fibroblast-derived cell lines to the New York Stem Cell Foundation (NYSCF), which were used to produce iPSCs (adult stem cells). These cell lines have been mostly completed by the beginning of September. Once created, the STAR team will work to differentiate these cells into Schwann cells (1A) and neuronal cells (Type 2). Dr. Baloh has begun a project for 2A and Dr. Gabsang Lee has begun project for 1A. Goal is to create a human assay suitable for evaluating potential targets of therapeutic intervention.

If you have questions pertaining to this STAR update, please contact Patrick Livney: or 1-312-750-9800.

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