Abstract Currently 1.5 billion people worldwide suffer from chronic pain. This number continues to increase as the elderly population grows, the prevalence of diabetes rises, and cancer survival rates improve. Chronic pain not only severely impacts daily quality of life for many patients, but it also places a heavy socioeconomic burden on society. With a lack of efficacious treatment options available, chronic pain is often treated with opioids. This is dangerous due to recent understanding of the extremely addictive and detrimental effects of opioids leading to the current opioid epidemic. Therefore, there is an urgent and clear unmet need for non-addictive alternative analgesics for the treatment of chronic pain. This need to find a solution to addictive opioids has brought interest to a particular sodium channel, NaV1.7, shown to be important for pain sensing. Gain-of-function mutations in NaV1.7 are associated with a disorder characterized by intense burning pain in the extremities: primary erythromelalgia. Conversely, loss-of function of NaV1.7 results in the inability to feel pain. Therefore, inhibiting NaV1.7 can be an effective method of reducing pain and treat erythromelalgia patients. To accomplish this, we designed epigenetic modulators to repress expression of SCN9A (encoding the NaV1.7 channel). Rather than making permanent edits to the genome, these epigenetic modulators will transiently inhibit expression of SCN9A. By targeting NaV1.7 at the DNA-level instead of the protein or RNA level, we can achieve specific and long-lasting modulation of NaV1.7, with better pharmacokinetics prospects than RNA- and protein-targeting approaches. In the parent CREATE grant, we propose to optimize these epigenetic modulators as well as their delivery to achieve high specificity and efficacy. The result of this study will be an optimized gene therapy that is not only non-addictive and efficacious for treatment of chronic pain but also highly specific and long-lasting. Although there is a clear market for a non-addictive therapy for chronic pain, we believe that a continued optimization of the AAV so that it can be delivered systemically instead of intrathecally will expand the patient population. This supplement will contribute to the optimization of the delivery of the therapy to improve the specificity and decrease manufacturing costs, which will translate to a more affordable therapy for patients.