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bioRxiv · 10.1101/2023.05.31.542947

Therapeutic TNF-alpha Delivery After CRISPR Receptor Modulation in the Intervertebral Disc

Stover, J. D.·Trone, M. A. R.·Weston, J.·Lewis, C.·Levis, H.·Philippi, M.·Zeidan, M.·Lawrence, B.·Bowles, R. D.
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Abstract

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 TNF- has multiple pathways and has been implicated as a primary mediator of disc degeneration. We tested our ability to regulate the multiple TNF- inflammatory signaling pathways in vivo utilizing CRISPR receptor modulation to slow the progression of disc degeneration in rats. Sprague-Dawley rats were treated with CRISPRi-based epigenome-editing therapeutics targeting TNFR1 and showed a decrease in behavioral pain in a disc degeneration model. Surprisingly, while treatment with the vectors alone was therapeutic, TNF- injection itself became therapeutic after TNFR1 modulation. These results suggest direct inflammatory receptor modulation, to harness beneficial inflammatory signaling pathways, as a potent strategy for treating disc degeneration.

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Stover, J. D., Trone, M. A. R., Weston, J., Lewis, C., Levis, H., Philippi, M., Zeidan, M., Lawrence, B., Bowles, R. D.. 2023-06-02. Therapeutic TNF-alpha Delivery After CRISPR Receptor Modulation in the Intervertebral Disc. https://doi.org/10.1101/2023.05.31.542947

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