Genome editing takes research one step closer to a cure for Charcot-Marie-Tooth disease

In the current issue of ACS Chemical Biology, Waisman Center, University of Wisconsin-Madison investigator, faculty director of the Cellular and Molecular Neurosciences Core, and professor of comparative biosciences, John Svaren, PhD’s paper “Genome editing-enabled HTS assays expand drug target pathways for Charcot-Marie-Tooth disease,” examines how the use of genome editing places his research one step closer to a potential cure for Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy that affects motor and sensory neurons, resulting in muscular atrophy, chronic pain and fatigue. CMT is one of the most common inherited neurological disorders, affecting approximately 1 in 3,000 people in the United States. Onset of CMT typically occurs in adolescence and, while it is not fatal, symptoms include mild to severe pain in addition to muscle weakness and atrophy in the limbs, eventually requiring bracing of lower limbs. Svaren’s CMT research aims to improve the myelin coating of peripheral nerves, which is adversely affected in CMT Type I, the most prevalent form.

Svaren’s research utilized recent advances in  genome editing—a process that can be used to modify genes—to insert an easily measured “meter” into a gene, Peripheral Myelin Protein 22 (abbreviated PMP22), which is duplicated in the most common form of CMT. The meter allows high throughput drug screening for novel compounds that can treat CMT. The ultimate goal is to attempt to modify a gene’s “signal” either “up” or “down,” thereby preventing the harmful effects caused by the PMP22 gene duplication. “This is a new way of drug screening,” said Svaren. “What we learned in our research can be made as a template for other disorders in which gene levels can be modified to effect a cure, and will allow us to determine the optimal way to prevent or halt progression of the symptoms associated with CMT.”

Svaren’s research was conducted in collaboration with James Inglese, PhD, director of the Assay Development and Screening Technology Laboratory at the National Center for Advancing Translational Sciences (NCATS). NCATS, which is part of the National Institutes of Health, was established to transform the translational science process so that new treatments and cures for disease can be delivered to patients faster. “NCATS collaborations can help accelerate the translation of molecular biology discoveries into potential treatments,” said Inglese. “This advance, which demonstrates the first use of genome editing to develop a cell line used in high-throughput screening, may serve to greatly accelerate the process of developing and deploying translational solutions that can be used broadly by the scientific community.”

Other collaborators included the CMT Association and Sangamo Biosciences, which has pioneered many advances in genome editing.

“There is a lot of excitement surrounding genome editing,” said Svaren. “This is the first application of genome editing technology coupled with a drug screening. We are part of a big technology wave, and are optimistic about finding a cure for CMT and other diseases based on our research.”