Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently dose-limiting side-effect of chemotherapeutic drugs. CIPN can be excruciatingly painful, profoundly debilitating, cause permanent disability, and lead some patients to elect to end life-saving treatment. In contrast to other side effects, CIPN frequently lasts well beyond the duration of treatment and can cause permanent disability. Consequently, therapies are urgently needed as they would not only enhance the quality of life of cancer patients both during and after treatment, but also improve cancer therapy by permitting effective chemotherapeutic dosing. To address this need we have developed mechanism-based interventional strategies for CIPN. Chemotherapy-induced neuropathies are characterized by axonal degeneration, which leads to the unpleasant symptoms of neuropathies. We have shown that vincristine and bortezomib, two widely used chemotherapeutic agents with different mechanisms of action act via the neuronal protein SARM1, the central executioner of a genetically encoded axon degeneration program. Activated SARM1 cleaves the metabolic cofactor NAD+, leading to local NAD+ depletion, followed by metabolic collapse and axon fragmentation. We here present several new strategies to block this final common pathway to axon degeneration. We generated a SARM1 dominant/negative that potently inhibits SARM1 function and axon degeneration. We will utilize adenoassociated virus (AAV) -mediated expression of a SARM1 dominant-negative to block SARM1 activity and will assess the effect of SARM1-dominant/negative on axon degeneration, neuroinflammation and functional outcomes. We have shown in vitro that boosting the synthesis of NAD+ strongly protects against vincristine and bortezomib-induced axon degeneration. We will use virus-mediated expression of enzymes of the NAD+ salvage pathway to boost NAD+ synthesis, which counters the axon destructive effects of SARM1. As a further step to translation to the clinic, we will evaluate in mouse models of cancer whether our therapeutic strategies interact with the cancer or chemotherapy and are effective in cancer-bearing mice. Success of our experiments will lead directly to clinically viable means to prevent and treat CIPN.