CMT1A is caused by a gene-copying event that results in the overproduction of the peripheral myelin protein 22 (PMP22) in Schwann cells. The excess PMP22 protein fails to traffic normally to the cell surface and instead collects inside the cells as clumps of proteins called “inclusions”, which disrupt the normal function of Schwann cells in producing myelin. Myelin is what constitutes the protective insulation wrapped around nerves.

This project by Dr. Sanders at Vanderbilt University seeks to discover lead molecules for development of drugs that can treat these underlying causes of CMT1A by optimizing the levels of PMP22 protein production in cells and/or by suppressing the tendency of PMP22 to form intracellular inclusions.

During year 1 of this project, Dr. Sanders and his team completed a screen of over 20,000 different compounds and succeeded in finding several molecules (“hits”) that alter PMP22 production and/or cell surface trafficking and are currently conducting studies to assess the potency and PMP22 protein binding ability of these hit compounds. This is a very promising year-1 start to this 3-year project.

In the upcoming project year, Dr. Sanders and his team will further assess the potency and efficacy of these hit compounds in Schwann cells. They will also develop and test new versions of these hit compounds in an attempt to discover additional compounds with even more activity on altering PMP22 production or trafficking and correcting myelination issues in Schwann cells, an important step in the progression toward eventually testing these compounds for their ability to prevent or relieve disease symptoms and pathology in CMT1A animal models.

As needed, they also will pursue additional compound screening in project year 2