Characterizing NaV1.7 antisense analgesia through antagonist binding, mRNA expression, and neuraxial distribution
4 affiliations
- 1Department of Anesthesiology, School of Medicine, UCSD, San Diego, California, USA.
- 2IONIS Pharmaceuticals, Inc., Carlsbad, California, USA.
- 3Department of Neurobiology, School of Biological Sciences, and
- 4Department of Neuroscience, School of Medicine, UCSD, San Diego, California, USA.
Abstract
Genome-targeting strategies to address NaV1.7-mediated signaling in nociceptive afferents are of great clinical interest given its high selectivity and persistent analgesic outcomes. In the present work, we analyze concentration-dependent effects of suppressing primary afferent NaV1.7 using the intrathecal delivery of an antisense oligonucleotide (ASO) on pain behaviors and demonstrate that NaV1.7 ASOs are likely to modulate pain traffic by blocking afferent signaling at the dorsal root ganglion (DRG) level. Intrathecal NaV1.7 ASOs induced a concentration-dependent gradient of knockdown in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488-ProTx-II binding in small DRG neurons, and a suppression of pain behaviors initiated by mechanical compression, inflammation, and the NaV1.7 agonist OD-1. The rostro-caudal reduction in mRNA correlated with ASO distribution, with implications for dose-related analgesic profiles. Marked reduction in DRG NaV1.7 binding was seen after intrathecal delivery of an ASO optimal dose, with high selectivity for small DRG neurons. Changes in sciatic nerve NaV1.7 binding were not detected, indicating a pain traffic modulation likely happening due to a block of afferent signaling at the DRG level.
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BibTeX
@article{malange2026characterizing,
title = {{Characterizing NaV1.7 antisense analgesia through antagonist binding, mRNA expression, and neuraxial distribution}},
author = {Kaue Malange and Julia Borges Paes Lemes and Briana Noble and Yuvicza Anchondo and Carlos E. Morado-Urbina and Saee Jadhav and Saurabh Yadav and Jingrui Ma and Vineet Augustine and Sara A. Dochnal and Chiraag Kambalimath and Marie Duong and Pedro Alvarez and Bethany Fitzsimmons and Curt Mazur and Holly B. Kordasiewicz and Kim Dore and Hien T. Zhao and Tony Yaksh},
journal = {JCI Insight},
year = {2026},
month = oct,
doi = {10.1172/jci.insight.196154},
url = {https://doi.org/10.1172/jci.insight.196154},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Characterizing NaV1.7 antisense analgesia through antagonist binding, mRNA expression, and neuraxial distribution
AU - Kaue Malange
AU - Julia Borges Paes Lemes
AU - Briana Noble
AU - Yuvicza Anchondo
AU - Carlos E. Morado-Urbina
AU - Saee Jadhav
AU - Saurabh Yadav
AU - Jingrui Ma
AU - Vineet Augustine
AU - Sara A. Dochnal
AU - Chiraag Kambalimath
AU - Marie Duong
AU - Pedro Alvarez
AU - Bethany Fitzsimmons
AU - Curt Mazur
AU - Holly B. Kordasiewicz
AU - Kim Dore
AU - Hien T. Zhao
AU - Tony Yaksh
PY - 2026
DA - 2026/10/22
JO - JCI Insight
DO - 10.1172/jci.insight.196154
UR - https://doi.org/10.1172/jci.insight.196154
AB - Genome-targeting strategies to address NaV1.7-mediated signaling in nociceptive afferents are of great clinical interest given its high selectivity and persistent analgesic outcomes. In the present work, we analyze concentration-dependent effects of suppressing primary afferent NaV1.7 using the intrathecal delivery of an antisense oligonucleotide (ASO) on pain behaviors and demonstrate that NaV1.7 ASOs are likely to modulate pain traffic by blocking afferent signaling at the dorsal root ganglion (DRG) level. Intrathecal NaV1.7 ASOs induced a concentration-dependent gradient of knockdown in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488-ProTx-II binding in small DRG neurons, and a suppression of pain behaviors initiated by mechanical compression, inflammation, and the NaV1.7 agonist OD-1. The rostro-caudal reduction in mRNA correlated with ASO distribution, with implications for dose-related analgesic profiles. Marked reduction in DRG NaV1.7 binding was seen after intrathecal delivery of an ASO optimal dose, with high selectivity for small DRG neurons. Changes in sciatic nerve NaV1.7 binding were not detected, indicating a pain traffic modulation likely happening due to a block of afferent signaling at the DRG level.
SN - 2379-3708
ER -