186. Translating an Optogenetic Gene Therapy Approach for Treatment of Neuropathic Pain in Humans

Optogenetics has been established as a powerful tool to study the central and peripheral nervous systems with its potential for directly treating human disease tantalizingly on the horizon. Optogenetic inhibition of pain in mice has been shown to be effective and provides an attractive initial application. We aim to translate this approach to treat neuropathic pain in humans. Firstly, we demonstrated that the inhibitory opsin, NpHR, delivered by intraneural injections of AAV6 could reduce pain (mechanical allodynia) in a clinically meaningful paradigm i.e. vector delivery after establishment of neuropathic pain in the chronic constriction injury (CCI) model. The inhibitory opsin, iC1C2 (a chloride channel requiring less light than NpHR to pass currents) could also reduce pain in this system. We next tested a surgical approach more amenable to patients than nerve injection. Lumbar puncture is a routine clinical practice and AAV8 delivery by this method results in efficient gene delivery to sensory neurons in rodents, dogs and pigs. We found that intrathecal administration of AAV8 expressing iC1C2 could decrease mechanical allodynia in the CCI mouse model. The magnitude of pain inhibition correlated with transduction levels and only 10% transduction of sensory neurons was required for pain relief. To further validate this approach we utilized a second rodent pain model with translational relevance. The mouse tibia fracture/cast immobilization model of Complex Regional Pain Syndrome (CRPS) presents extreme allodynia and recapitulates human disease effectively. We found that intrathecal delivery of AAV8 encoding iC1C2 following development of the CRPS model resulted in light-mediated pain inhibition. Taken together, our results confirm optogenetic therapy for neuropathic pain as an attractive clinical application of this technology.