AAV9-tRNA-Gly: Towards a first effective therapy for Charcot-Marie-Tooth peripheral neuropathy

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disease, characterized by selective degeneration of peripheral motor and sensory neurons, leading to progressive muscle weakness and wasting, and sensory dysfunction. Currently, no effective, FDA/EMA-approved therapies are available for CMT, necessitating life-long symptomatic treatment. We recently identified the molecular mechanism underlying CMT caused by mutations in glycyl-tRNA synthetase (GlyRS). We showed that transgenic overexpression of the glycyl-transfer RNA (tRNA-Gly) fully rescues peripheral neuropathy in two CMT-GlyRS mouse models. Furthermore, we present preliminary data showing that viral vector-mediated gene transfer of tRNA-Gly administered to newborn, presymptomatic CMT-GlyRS mice fully rescues their peripheral neuropathy phenotypes. In this project we will optimize tRNA-Gly gene therapy, including identification of the optimal viral vector, administration route, and dose to target adult motor and sensory neurons. Next to that, the project will focus on the development of a business roadmap for XtRNA Bio, the spin-out company that I recently co- founded with NLC Health Ventures. XtRNA Bio intends to raise significant pre-seed funding and recruit presonnel, including an experienced CEO who will secure additional funds for continued preclinical and clinical development of tRNA-Gly gene therapy. Finally, once identified, we will patent the optimal gene therapy construct. In all, this proposal constitutes a crucial step towards a first effective therapy for CMT-GlyRS and CMT in general.