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 1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na 1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na 1.7 functi...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 32; p. e2217800120 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
08.08.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na
1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na
1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na
1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na
1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na
1.7 CRS over other Na
isoforms. Substitution of the Na
1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na
1.7 currents. A cell-penetrant decoy peptide corresponding to the Na
1.7-CRS reduced Na
1.7 currents and trafficking, decreased presynaptic Na
1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na
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
1.7 -targeted gene therapy, we packaged a plasmid encoding the Na
1.7-CRS in an AAV virus. Treatment with this virus reduced Na
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. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.2217800120 |