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The degenerative intervertebral disc (IVD) has been hypothesized to contribute to discogenic pain by sensitizing nociceptive neurons innervating the disc to stimuli that is nonpainful in healthy patients. Previously, we demonstrated the ability of degenerative IVDs to sensitize neurons to mechanical stimuli; however, elucidation of degenerative IVDs discogenic pain mechanisms is required to develop therapeutic strategies that directly target these mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>In this study, we utilized CRISPR epigenome editing of nociceptive neurons to identify mechanisms of degenerative IVD\u2010induced changes to mechanical nociception and demonstrated the ability of multiplex CRISPR epigenome editing of nociceptive neurons to modulate inflammation\u2010induced mechanical nociception.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Utilizing an in vitro model, we demonstrated degenerative IVD\u2010produced IL\u20106\u2010induced increases in nociceptive neuron activity in response to mechanical stimuli, mediated by TRPA1, ASIC3, and Piezo2 ion channel activity. Once these ion channels were identified as mediators of degenerative IVD\u2010induced mechanical nociception, we developed singleplex and multiplex CRISPR epigenome editing vectors that modulate endogenous expression of TRPA1, ASIC3, and Piezo2 via targeted gene promoter histone methylation. When delivered to nociceptive neurons, the multiplex CRISPR epigenome editing vectors abolished degenerative IVD\u2010induced mechanical nociception while preserving nonpathologic neuron activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This work demonstrates the potential of multiplex CRISPR epigenome editing as a highly targeted gene\u2010based neuromodulation strategy for the treatment of discogenic pain, specifically; and, for the treatment of inflammatory chronic pain conditions, more broadly.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsp2.1253","type":"journal-article","created":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T03:58:55Z","timestamp":1679111935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multiplex epigenome editing of ion channel expression in nociceptive neurons abolished degenerative <scp>IVD<\/scp>\u2010conditioned media\u2010induced mechanical 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