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

Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV 1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV 1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV 1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV 1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV 1.7 CRS over other NaV isoforms. Substitution of the NaV 1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased NaV 1.7 currents. A cell-penetrant decoy peptide corresponding to the NaV 1.7-CRS reduced NaV 1.7 currents and trafficking, decreased presynaptic NaV 1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the NaV 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 NaV 1.7 -targeted gene therapy, we packaged a plasmid encoding the NaV 1.7-CRS in an AAV virus. Treatment with this virus reduced NaV 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.