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Papers of the Week

Papers: 22 Jul 2023 - 28 Jul 2023

Basic Science

Animal Studies, Molecular/Cellular, Neurobiology, Pharmacology/Drug Development

Neuropathic Pain

2023 Aug 08

Proc Natl Acad Sci U S A




Editor's Pick

Identification and targeting of a unique Na1.7 domain driving chronic pain.


Gomez K, Stratton HJ, Duran P, Loya S, Tang C, Calderon-Rivera A, François-Moutal L, Khanna M, Madura CL, Luo S, McKiver B, Choi E, Ran D, Boinon L, Perez-Miller S, Damaj MI, Moutal A, Khanna R


Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na1.7 CRS over other Na isoforms. Substitution of the Na1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na1.7 currents. A cell-penetrant decoy peptide corresponding to the Na1.7-CRS reduced Na1.7 currents and trafficking, decreased presynaptic Na1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na1.7-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 Na1.7 -targeted gene therapy, we packaged a plasmid encoding the Na1.7-CRS in an AAV virus. Treatment with this virus reduced Na1.7 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.