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Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury

Year: 2021
Type: article
Abstract: 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.
DOI: 10.1038/s41598-021-82951-5
Authors: J. R. Huie, A. R. Ferguson, N. Kyritsis, J. Z. Pan, K.-A. Irvine, J. L. Nielson, P. G. Schupp, M. C. Oldham, J. C. Gensel, A. Lin, M. R. Segal, R. R. Ratan, J. C. Bresnahan, M. S. Beattie
Institutions: University of California, San Francisco, San Francisco VA Medical Center, VA Palo Alto Health Care System, Stanford Medicine, Stanford University, University of Minnesota, University of Kentucky, Cornell University, Weill Cornell Medicine
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $1,990
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of Mental Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: Metaplasticity and Recovery After Spinal Cord Injury: Cellular Mechanisms, G1615019242, G1982570615, G235943272, G259199465, G3062806406, G357620464, G4054923381, G4298046421, G617707123, G648697459, G661427347, Cervical spinal injury and demyelination in aged rats, Decoding the molecular basis of cellular identity in the human brain, G9000009461, G9000024064, G9000082746, G9000089157
OpenAlex ID: W3127099942
FWCI: 1.573
Cites: 55
Cited by: 13
Related to: 10