ABSTRACT Chronic pain is pain that persists past the normal time of healing. 1.5 billion people worldwide suffer from chronic pain and 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, it also places a heavy socioeconomic burden on society. Due to the limited number of efficacious treatment options available, chronic pain is often treated with opioids despite the risk of addiction and side effects. Unfortunately, the prescribing of opioids to treat chronic pain has largely fueled the current opioid epidemic. Therefore, there is an urgent and clear unmet need for non-addictive alternative analgesics for the treatment of chronic pain. The push to develop specific and non-addictive alternative painkillers 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 NaV1.7. Rather than making permanent edits to the genome, these epigenetic modulators will transiently inhibit expression of NaV1.7. By targeting NaV1.7 at the DNA-level, we can achieve specific and long-lasting modulation of NaV1.7, with better pharmacokinetics prospects than RNA- and protein-targeting approaches. In this study, we propose to optimize these epigenetic modulators as well as their delivery in order to achieve high specificity and efficacy. In addition, we will evaluate our optimized modulators in small-scale manufacturing studies as well as toxicological studies in a large animal model. 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.