SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration.

Axonal degeneration contributes to the pathogenesis of many neurodegenerative disorders, motivating efforts to dissect the mechanism of pathological axon loss in order to develop therapies for axonal preservation. SARM1 is a particularly attractive therapeutic target, as it is an inducible NAD+ cleaving enzyme that is required for axon loss in multiple mouse models of traumatic and degenerative neurological disease. However, it is essential to establish whether SARM1 triggers axon degeneration in human neurons before proceeding with the development of SARM1-directed therapeutics. Here we combine genome engineering with the production of human stem cell-derived neurons to test the role of human SARM1 in traumatic and neurotoxic axon degeneration. We have generated two independent SARM1 knockout human iPSC lines that do not express SARM1 protein upon differentiation into neurons. We have developed a modified sensory neuron differentiation protocol that generates human sensory neurons with high yield and purity. We find that SARM1 is required for axon degeneration in response to both physical trauma and in a cellular model of chemotherapy-induced peripheral neuropathy. Finally, we identify cADPR as a biomarker of SARM1 enzyme activity in both healthy and injured human sensory neurons. These findings are consistent with prior molecular and cellular studies in mouse neurons, and highlight the therapeutic potential of SARM1 inhibition for the prevention and treatment of human neurological disease.