CMT2A is caused by dominant mutations in MFN2. It has been shown that MFN1 can compensate for MFN2 in cell models, and the over-expression of MFN1 can even compensate for the effects of dominant MFN2 mutants. Thus, the goal is to be able to use high-throughput screening (HTS) to identify small molecules that up-regulate the expression of MFN1 in human neuronal cell lines and determine whether they can rescue the effects of dominant MFN2 mutants in cells derived from CMT2A patients and in laboratory models of CMT2A.

A CMT2A drug screening assay validated by Dr. Brittany Wright, working in Dr. James Inglese’s lab at the NIH, is being prepared for evaluation and introduction into pilot testing.

Work is ongoing to characterize new genetic animal models of CMT2A. This is a broad cross-functional consortium effort involving a number of specializations contributed by STAR investigator labs and alliance partners, including: Animal genetics at Horizon Discovery; breeding and cryopreservation at Charles River; behavioral analysis at PsychoGenics; physiology, histology and electron microscopy in Dr. Steven Scherer’s lab at the University of Pennsylvania; and molecular regulation studies in Dr. Robert Baloh’s lab at Cedars-Sinai Medical Center.  At present, models have been identified for two human mutations. Disease-associated behavioral and histopathological defects have been confirmed.