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- W4212960432 abstract "Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. PMID: 33692134 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: R43 NS112088 NHGRI NIH HHS, United States Grant ID: R01 HG009285 NCI NIH HHS, United States Grant ID: R01 CA222826 NINDS NIH HHS, United States Grant ID: U44 NS122114 NIGMS NIH HHS, United States Grant ID: R01 GM123313 NINDS NIH HHS, United States Grant ID: R01 NS102432 NCI NIH HHS, United States Grant ID: R43 CA239940 More Less keyboard_arrow_down" @default.
- W4212960432 created "2022-02-24" @default.
- W4212960432 creator A5056553144 @default.
- W4212960432 date "2021-05-02" @default.
- W4212960432 modified "2023-09-27" @default.
- W4212960432 title "Faculty Opinions recommendation of Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice." @default.
- W4212960432 doi "https://doi.org/10.3410/f.739716092.793585210" @default.
- W4212960432 hasPublicationYear "2021" @default.
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