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

Journal: Scientific reports
PMID: 33564058

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.

Authors

  • J R Huie
    Department of Neurological Surgery, Brain and Spinal Injury Center (BASIC), University of California, San Francisco, CA, USA.
  • A R Ferguson
    Department of Neurological Surgery, Brain and Spinal Injury Center (BASIC), University of California, San Francisco, CA, USA. adam.ferguson@ucsf.edu.
  • N Kyritsis
    Neurological Surgery (R.J.H., A.F., X.D.-F., L.H.T., N.K., M.S.B., J.C.B., S.D., W.W., J.F.T.).
  • J Z Pan
    Department of Anesthesiology, University of California San Francisco, San Francisco, USA.
  • K-A Irvine
    Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
  • J L Nielson
    Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, USA.
  • P G Schupp
    Brain Tumor Research Center, University of California, San Francisco, USA.
  • M C Oldham
    Brain Tumor Research Center, University of California, San Francisco, USA.
  • J C Gensel
    SCoBIRC, University of Kentucky, Lexington, USA.
  • A Lin
    Department of Neurological Surgery, Brain and Spinal Injury Center (BASIC), University of California, San Francisco, CA, USA.
  • M R Segal
    Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California San Francisco, San Francisco, USA.
  • R R Ratan
    Department of Neurology and Neuroscience, Burke-Cornell Medical Research Institute, Weill Medical College of Cornell University, New York, USA.
  • J C Bresnahan
    Neurological Surgery (R.J.H., A.F., X.D.-F., L.H.T., N.K., M.S.B., J.C.B., S.D., W.W., J.F.T.).
  • M S Beattie
    Neurological Surgery (R.J.H., A.F., X.D.-F., L.H.T., N.K., M.S.B., J.C.B., S.D., W.W., J.F.T.).

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