Long-lasting analgesia via targeted in situ repression of Na(V)1.7 in mice

Autor(es):Mostrar menos -

Moreno, Ana M. ^{[1, 2]} ; Aleman, Fernando ^{[1, 2]} ; Catroli, Glaucilene F. ^[3] ; Hunt, Matthew ^[3] ; Hu, Michael ^[1] ; Dailamy, Amir ^[1] ; Pla, Andrew ^[1] ; Woller, Sarah A. ^{[3, 4]} ; Palmer, Nathan ^[5] ; Parekh, Udit ^[6] ; McDonald, Daniella ^{[1, 7]} ; Roberts, Amanda J. ^[8] ; Goodwill, Vanessa ^[9] ; Dryden, Ian ^[9] ; Hevner, Robert F. ^[9] ; Delay, Lauriane ^[3] ; dos Santos, Gilson Goncalves ^[3] ; Yaksh, Tony L. ^[3] ; Mali, Prashant ^[1]

Afiliação do(s) autor(es)

^[1] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92093 - USA

^[2] Navega Therapeut, San Diego, CA 92121 - USA

^[3] Univ Calif San Diego, Dept Anesthesiol, San Diego, CA 92093 - USA

^[4] NINDS, NIH, Bethesda, MD 20852 - USA

^[5] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92093 - USA

^[6] Univ Calif San Diego, Dept Elect Engn, San Diego, CA 92093 - USA

^[7] Univ Calif San Diego, Biomed Sci Grad Program, San Diego, CA 92093 - USA

^[8] Scripps Res Inst, Anim Models Core, La Jolla, CA 92037 - USA

^[9] Univ Calif San Diego, Dept Neuropathol, San Diego, CA 92093 - USA

• Tipo de documento: Artigo Científico
• Fonte: Science Translational Medicine; v. 13, n. 584 MAR 10 2021.
• Citações Web of Science: 1

Resumo

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 Na(V)1.7, 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-V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na(V)1.7 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 Na(V)1.7 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 Na(V)1.7 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 Na(V)1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states. (AU)

• Processo FAPESP: 18/05778-3 - O papel da sinalização do receptor purinérgico P2X4 dos gânglios da raiz dorsal e da medula espinhal na alodinia inicial e tardia no modelo de inflamação crônica em camundongos K/BxN
• Beneficiário: Glaucilene Ferreira Catroli
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado