Project Summary: The primary goal of this R21/R33 Translational Aging Research Identification award is develop, optimize, and validate a novel gene therapy-based treatment approach for refractory pain in older individuals. Pain is a major socioeconomic problem, affecting more than 25% of adults in the US. The lack of effective treatments for pain has fueled the opioid epidemic. In elderly patients, treatment options are even more limited, on account of medical conditions that prevent specific drug use as well as increased risks of side effects due to polypharmacy. Evidence from human genetics and mouse models suggests that reducing firing in primary pain-sensing neurons, nociceptors, is sufficient to abrogate pain. We first design new mechanisms for delivering to AAVs specifically to nociceptors. We then develop novel approaches to decrease nociceptor firing, and we validate this reduction using whole cell patch clamp electrophysiology in both primary mouse nociceptors and nociceptors derived from human induced pluripotent stem cells. We validate pain models in aged animals, and obtain proof- of-concept efficacy for the AAV-based treatment strategy using the pain models in aged animals. The successful completion of the project sets the stage for continued preclinical development of AAV-based therapy for refractory pain in older individuals.