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Papers of the Week

Papers: 6 Mar 2021 - 12 Mar 2021

Animal Studies, Pharmacology/Drug Development

2021 Mar 10

Sci Transl Med



Long-lasting analgesia via targeted in situ repression of Na1.7 in mice.


M Moreno A, Alemán F, Catroli GF, Hunt M, Hu M, Dailamy A, Pla A, Woller SA, Palmer N, Parekh U, McDonald D, Roberts AJ, Goodwill V, Dryden I, Hevner RF, Delay L, Dos Santos G G, Yaksh TL, Mali P
Sci Transl Med. 2021 Mar 10; 13(584).
PMID: 33692134.


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 Na1.7, 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 Na subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na1.7 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 Na1.7 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 Na1.7 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 Na1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.