Therapeutic CRISPR epigenome editing of inflammatory receptors in the intervertebral disc

• Published in: Molecular therapy Vol. 32; no. 11; pp. 3955 - 3973
• Main Authors: Stover, Joshua D., Trone, Matthew A.R., Weston, Jacob, Lewis, Christian, Levis, Hunter, Farhang, Niloofar, Philippi, Matthew, Zeidan, Michelle, Lawrence, Brandon, Bowles, Robby D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2024
• Subjects: CRISPR; degenerative disc disease; gene therapy; inflammatory cytokine signaling; intervertebral disc; low back pain; TNFR1; CRISPR; degenerative disc disease; intervertebral disc; low back pain; gene therapy; inflammatory cytokine signaling; TNFR1
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2024.09.022

Low back pain (LBP) ranks among the leading causes of disability worldwide and generates a tremendous socioeconomic cost. Disc degeneration, a leading contributor to LBP, can be characterized by the breakdown of the extracellular matrix of the intervertebral disc (IVD), disc height loss, and inflammation. The inflammatory cytokine tumor necrosis factor α (TNF-α) has multiple signaling pathways, including proinflammatory signaling through tumor necrosis factor receptor 1 superfamily, member 1a (TNFR1 or TNFRSF1A), and has been implicated as a primary mediator of disc degeneration. We tested our ability to regulate the TNFR1 signaling pathway in vivo, utilizing CRISPR epigenome editing to slow the progression of disc degeneration in rats. Sprague-Dawley rats were treated with TNF-α and CRISPR interference (CRISPRi)-based epigenome-editing therapeutics targeting TNFR1, showing decreased behavioral pain in a disc degeneration model. Surprisingly, while treatment with the vectors alone was therapeutic, the TNF-α injection became therapeutic after TNFR1 modulation. These results suggest direct inflammatory receptor modulation as a potent strategy for treating disc degeneration. [Display omitted] Stover and colleagues used CRISPR-based epigenome editing targeting TNFR1 to successfully reduce disc degeneration and pain in a rat model of degenerative disc disease. This study highlights direct inflammatory receptor modulation as a promising therapeutic strategy for treating low back pain caused by disc degeneration.