Project Summary/Abstract The goal of this project is to develop a gene therapy product that relieves chemotherapy-induced peripheral neuropathy (CIPN) in a non-permanent, non-addictive and long-lasting manner to improve the quality of life of cancer patients. Current management of CIPN and cancer pain is very poor, with 1 in 3 patients not receiving pain medication considered appropriate for the intensity of pain experienced. With the limited efficacious treatment options available, opioids are often prescribed, however these can lead to addiction. We are in urgent need of novel pain therapies that would alleviate the side effects of opioids. Voltage- gated sodium channels (NaV family) have been used in nociceptive transmission and contribution to the hyperexcitability in primary afferent nociceptive neurons. Additionally, many chemotherapy agents induce ion channel expression including NaV1.7 and NaV1.8, leading to CIPN. Hence, these sodium channels have been attractive targets for developing chronic pain therapies. However, the high homology of human NaV proteins has frustrated most efforts to develop selective protein inhibitors. Instead of targeting the protein, Navega proposes to develop a non-permanent epigenome regulation tool to target pain. This novel approach is non-addictive, highly specific, and long-lasting. During Phase I, we determined that the simultaneous inhibition of NaV1.7 and NaV1.8, was more efficacious at reversing CIPN than repressing each channel alone. We also demonstrated the safety of our approach at doses tested in mice. During Phase II we will: 1) perform dose-range studies in mice to determine the therapeutic window; 2) optimize our reagents to target the human genome; and 3) perform GLP definitive safety studies in NHPs. We will prepare an IND application to the FDA, and will submit it at the end of the Phase II project. Our final goal is to develop novel therapeutics that can mitigate CIPN through the use of a specific gene therapy approach that can simultaneously target two voltage gated sodium channels (something not possible with small molecules) and provide an alternative treatment to opioids for patients with chronic pain.