Phase II year
2021
(last award dollars: 2022)
Phase II Amount
$2,577,902
Chronic pain is pain that persists past the normal time of healing. 1.5 billion peopleworldwide suffer from chronic pain and this number continues to increase as the elderly populationgrows, the prevalence of diabetes rises, and cancer survival rates improve. Chronic pain not onlyseverely impacts daily quality of life for many patients, it also places a heavy socioeconomicburden on society. Due to the limited number of efficacious treatment options available, chronicpain is often treated with opioids despite the risk of addiction and side effects. Unfortunately, theprescribing 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 forthe treatment of chronic pain. The push to develop specific and non-addictive alternativepainkillers has brought interest to a particular sodium channel, NaV1.7, shown to be important forpain sensing. Gain-of-function mutations in NaV1.7 are associated with a disorder characterizedby intense burning pain in the extremities: primary erythromelalgia. Conversely, loss-of functionof NaV1.7 results in the inability to feel pain. Therefore, inhibiting NaV1.7 can be an effectivemethod of reducing pain and treat erythromelalgia patients. To accomplish this, we designedepigenetic modulators to repress expression of NaV1.7. Rather than making permanent edits tothe genome, these epigenetic modulators will transiently inhibit expression of NaV1.7. By targetingNaV1.7 at the DNA-level, we can achieve specific and long-lasting modulation of NaV1.7, withbetter pharmacokinetics prospects than RNA- and protein-targeting approaches. In this study, wepropose to optimize these epigenetic modulators as well as their delivery in order to achieve highspecificity and efficacy. In addition, we will evaluate our optimized modulators in small-scalemanufacturing studies as well as toxicological studies in a large animal model. The result of thisstudy will be an optimized gene therapy that is not only non-addictive and efficacious for treatmentof chronic pain but also highly specific and long-lasting.
Public Health Relevance Statement: PROJECT NARRATIVE
Due to the lack of efficacious alternative treatment options, chronic pain is often treated with
opioids despite the risk of addiction and side effects. With the advent of gene therapy, it is now
possible to specifically target pain pathways at the molecular level. The goal of this study is to
further develop and evaluate the efficacy and safety of a non-addictive, alternative analgesic that
can epigenetically repress expression of NaV1.7, a sodium channel that is important for sensing
pain.
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