Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining five different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 h after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target.
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This work was funded by NIH Grants NS067092 (A.R.F.), NS088475 (A.R.F), VA grants I01RX002787 and I01RX002245 (A.R.F.), NS038079 (J.C.B. and M.S.B.), AG032518 (M.S.B. and J.C.B.), NYSCoRE CO19772 (M.S.B. and J.C.B.), and NIH UCSF Anesthesia T32 training grant (NIGMS T32GM008440) to JZP.
Huie, J. R.; Ferguson, A. R.; Kyritsis, N.; Pan, J. Z.; Irvine, K.-A.; Nielson, J. L.; Schupp, P. G.; Oldham, M. C.; Gensel, John C.; Lin, A.; Segal, M. R.; Ratan, R. R.; Bresnahan, J. C.; and Beattie, M. S., "Machine Intelligence Identifies Soluble TNFa as a Therapeutic Target for Spinal Cord Injury" (2021). Spinal Cord and Brain Injury Research Center Faculty Publications. 36.