Therapeutic CRISPR epigenome editing of inflammatory receptors in the intervertebral disc.

Autor:	Stover JD; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Trone MAR; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Weston J; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Lewis C; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Levis H; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Farhang N; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA., Philippi M; Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA., Zeidan M; Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA., Lawrence B; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA., Bowles RD; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: robert.bowles@utah.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Nov 06; Vol. 32 (11), pp. 3955-3973. Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1016/j.ymthe.2024.09.022
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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