Identification and targeting of a unique Na V 1.7 domain driving chronic pain.

Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na V 1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na V 1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na V 1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na V 1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na V 1.7 CRS over other Na V isoforms. Substitution of the Na V 1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na V 1.7 currents. A cell-penetrant decoy peptide corresponding to the Na V 1.7-CRS reduced Na V 1.7 currents and trafficking, decreased presynaptic Na V 1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na V 1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a Na V 1.7 -targeted gene therapy, we packaged a plasmid encoding the Na V 1.7-CRS in an AAV virus. Treatment with this virus reduced Na V 1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.