Identification and targeting of a unique NaV1.7 domain driving chronic pain

Gomez, K.; Stratton, H. J.; Duran, P.; Loya, S.; Tang, C.; Calderon-Rivera, A.; Francois-Moutal, L.; Khanna, M.; Madura, C. L.; Luo, S.; Ran, D.; Boinon, L.; Perez-Miller, S.; Moutal, A.; Khanna, R.

doi:10.1101/2022.07.09.499431

bioRxiv · 10.1101/2022.07.09.499431

Identification and targeting of a unique NaV1.7 domain driving chronic pain

Gomez, K.·Stratton, H. J.·Duran, P.·Loya, S.·Tang, C.·Calderon-Rivera, A.·Francois-Moutal, L.·Khanna, M.·Madura, C. L.·Luo, S.·Ran, D.·Boinon, L.·Perez-Miller, S.·Moutal, A.·Khanna, R.

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Abstract

Despite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition of a small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered a 15 amino acid CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight voltage-gated sodium channel isoforms decreased tetrodotoxin-sensitive NaV1.7 currents in rodent sensory neurons. A cell-penetrant version of NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 localization, reduced spinal neurotransmitter release, and reversed mechanical allodynia in a rat spared nerve injury model of neuropathic pain. Interfering with NaV1.7-CRMP2 coupling did not produce motor impairment and spared thermal, inflammatory, and post-surgical nociception. As proof-of-concept for NaV1.7-targeted gene therapy, we found that NaV1.7-CRS packaged into an adeno-associated virus recapitulated the effects on NaV1.7 function in both rodent and rhesus macaque sensory neurons and both reversed and prevented the development of mechanical allodynia in a neuropathic pain model in male and female rodents. One Sentence SummaryA novel regulatory domain on the voltage gated sodium channel NaV1.7 that can be targeted to produce analgesia.

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Gomez, K., Stratton, H. J., Duran, P., Loya, S., Tang, C., Calderon-Rivera, A., Francois-Moutal, L., Khanna, M., Madura, C. L., Luo, S., Ran, D., Boinon, L., Perez-Miller, S., Moutal, A., Khanna, R.. 2022-07-10. Identification and targeting of a unique NaV1.7 domain driving chronic pain. https://doi.org/10.1101/2022.07.09.499431

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