CMT Type 1A is caused by the duplication of the Peripheral Myelin Protein 22 (PMP22) gene, which leads to the demyelination of the peripheral nerves. The research to date has focused on finding small molecules that interact with specific molecular targets to downregulate the production of PMP22 or to correct a downstream defect of PMP22 overproduction.

Sanofi’s U.S. screening center finished screening the 1.9 million compounds in its repository in early 2015, using a cell-based assay that reports the activation of the gene for PMP22 by emitting a light signal. Further work has distilled the screen results down to those small molecules that are specific for the regulation of PMP22 and that don’t regulate other myelin proteins. A number of specific targets have been identified with molecules that target them.  This team effort involves a number of STAR investigator groups at the Universities of Wisconsin, Buffalo, Johns Hopkins and the NIH, working together with teams of investigators from Genzyme and Sanofi (U.S.).

The National Institutes of Health has also used the cell-based reporter assay to complete its own 400,000 small molecule screen using the NIH Small Molecule Repository. They are currently conducting further screening on 10,000 of those compounds to confirm their activity. This work has been supported by a NIH grant to Dr. John Svaren at the University of Wisconsin, with additional support from the CMTA.

Preclinical investigation to validate the role of several pharmacological approaches to ameliorate the effects of PMP22 overexpression has taken a big step forward in 2015. Alliance partners Addex and Affectis have provided drug candidates to the molecular targets GABAb and P2X7, respectively. We have also pursued in vivo follow-up studies to a previously identified class of proteasome inhibitor.  The GABAb and P2X7 targets were earlier reported to be causally linked to PMP22 function in Schwann cells, and clinical development candidates that specifically regulate their function are already available via our alliances.  Work has also been successful this year in progressing drug candidates for all three target classes towards an in vivo proof-of-principle that shows the pathology of CMT1A can be chronically regulated in genetic animal models of the disease.  PsychoGenics is our CRO (contract research organization) alliance partner performing the investigational studies in rat and mouse models of CMT1A.

The lab of Dr. Gabsang Lee at Johns Hopkins University is advancing work on differentiating human stem cells from CMT1A patients into mature, myelinating Schwann cells. This is part of a STAR consortium effort with the NY Stem Cell Foundation to create induced pluripotent stem cell lines (iPSC) to rigorous standards from patient skin cells, and introduce them into CMTA investigational work. The Hopkins lab is also working to introduce new iPSC cell line methods into drug candidate testing being used in our alliances.

The careful in vitro assessment of candidate drugs is an essential piece of each STAR alliance effort going forward. For this, reason the CMTA has commissioned Dr. Laura Feltri’s lab at the University of Buffalo to regularly produce co-cultures of nerve and Schwann cells that actively form myelin. The evaluation of myelin marker response in this system to the treatment of candidate drugs is ongoing in support of our sponsored research and alliance activities.

Going forward, robust biomarkers of CMT1A disease progression are needed to aid patient selection for clinical trials, and to evaluate drug responsiveness. For this reason, Dr. John Svaren’s lab at the University of Wisconsin has been working to expand our knowledge of how Schwann cell–specific molecules are regulated in CMT1A as a reporter of defective myelination.