Charcot-Marie-Tooth Disease (CMT), is a heterogeneous collection of inherited neuropathies generally characterized by progressive muscle wasting. Currently incurable, it is the most common inherited disease of the peripheral nervous system, affecting 1:2,500 individuals worldwide. Over 1,000 mutations in 80 different loci in the human genome have been linked to specific subtypes of CMT. This suggests that there are many and diverse pathological pathways that cause individual forms of CMT and conspires against a single effective therapy for all patients. Thus, personalized genetic approaches may represent a more efficacious therapeutic strategy. My research focuses on developing personalized gene therapies that target the specific genetic mutations that cause neuropathy in individual patients with CMT.
I am piloting this approach with CMT Type 2D (CMT2D), a dominantly-inherited neuropathy caused by toxic mutations in the gene that encodes glycyl-tRNA synthetase (GARS). By expressing therapeutic microRNAs that target individual mutant Gars transcripts for degradation in a humanized mouse model of CMT2D that I developed using CRISPR/Cas9 genome-editing, I can halt the progression of axon degeneration and reverse neuropathy symptoms. This could be the first treatment for CMT2D, or any form of CMT, and will have broad applications for other dominantly inherited neuromuscular disorders.