PT  - JOURNAL ARTICLE
AU  - Moreno, Ana M.
AU  - Alemán, Fernando
AU  - Catroli, Glaucilene F.
AU  - Hunt, Matthew
AU  - Hu, Michael
AU  - Dailamy, Amir
AU  - Pla, Andrew
AU  - Woller, Sarah A.
AU  - Palmer, Nathan
AU  - Parekh, Udit
AU  - McDonald, Daniella
AU  - Roberts, Amanda J.
AU  - Goodwill, Vanessa
AU  - Dryden, Ian
AU  - Hevner, Robert F.
AU  - Delay, Lauriane
AU  - Gonçalves dos Santos, Gilson
AU  - Yaksh, Tony L.
AU  - Mali, Prashant
TI  - Long-lasting analgesia via targeted in situ repression of Na<sub>V</sub>1.7 in mice
AID  - 10.1126/scitranslmed.aay9056
DP  - 2021 Mar 10
TA  - Science Translational Medicine
PG  - eaay9056
VI  - 13
IP  - 584
4099  - http://stm.sciencemag.org/content/13/584/eaay9056.short
4100  - http://stm.sciencemag.org/content/13/584/eaay9056.full
AB  - Opioids are the current standard of care for the treatment of chronic pain. However, they have severe side effects. Recent data have shown that loss-of-function mutations in the sodium channel NaV1.7 cause insensitivity to pain. Here, Moreno et al. developed an epigenetic strategy using CRISPR-dCas9 and zinc fingers called long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 (LATER) to repress NaV1.7. In vivo, LATER reduced hyperalgesia in multiple animal models and reversed chemotherapy-induced chronic pain in mice. The results suggest that LATER might be effective for treating chronic pain of multiple origins.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.