Intravenous Administration of an AAV9 Vector Ubiquitously Expressing C1orf194 Gene Improved CMT-Like Neuropathy in C1orf194 Mice.

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of rare genetically heterogenous diseases characterized by progressive muscle weakness and atrophy, along with sensory deficits. Despite extensive pre-clinical and clinical research, no FDA-approved therapy is available for any CMT type. We previously identified C1ORF194, a novel causative gene for CMT, and found that both C1orf194 knock-in (I121N) and knockout mice developed clinical phenotypes similar to those in patients with CMT. Encouraging results of adeno-associated virus (AAV)-mediated gene therapy for spinal muscular atrophy have stimulated the use of AAVs as vehicles for CMT gene therapy. Here, we present a gene therapy approach to restore C1orf194 expression in a knockout background. We used C1orf194 mice treated with AAV serotype 9 (AAV9) vector carrying a codon-optimized WT human C1ORF194 cDNA whose expression was driven by a ubiquitously expressed chicken β-actin promoter with a CMV enhancer. Our preclinical evaluation demonstrated the efficacy of AAV-mediated gene therapy in improving sensory and motor abilities, thus achieving largely normal gross motor performance and minimal signs of neuropathy, on the basis of neurophysiological and histopathological evaluation in C1orf194 mice administered AAV gene therapy. Our findings advance the techniques for delivering therapeutic interventions to individuals with CMT.