{"doi":"10.1101/2020.07.22.216572","title":"Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury","abstract":"SUMMARY 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 1,2 . Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining 5 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 3 (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 hrs 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":130448,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":19292,"name":"Adam R. Ferguson","orcid":"0000-0001-7102-1608","position":1,"is_corresponding":false},{"id":296154,"name":"Nikos Kyritsis","orcid":"0000-0001-7801-5796","position":2,"is_corresponding":false},{"id":296165,"name":"Jonathan Z. Pan","orcid":"0000-0001-5814-3707","position":3,"is_corresponding":false},{"id":583120,"name":"Karen‐Amanda Irvine","orcid":"0000-0001-5259-1824","position":4,"is_corresponding":false},{"id":576801,"name":"Jessica L. Nielson","orcid":"0000-0002-3677-3959","position":5,"is_corresponding":false},{"id":583744,"name":"PG Schupp","orcid":null,"position":6,"is_corresponding":false},{"id":296171,"name":"Michael C. Oldham","orcid":"0000-0001-7633-6932","position":7,"is_corresponding":false},{"id":583745,"name":"JC Gensel","orcid":null,"position":8,"is_corresponding":false},{"id":583746,"name":"Amity Lin","orcid":null,"position":9,"is_corresponding":false},{"id":583747,"name":"MR Segal","orcid":null,"position":10,"is_corresponding":false},{"id":583748,"name":"RR Ratan","orcid":null,"position":11,"is_corresponding":false},{"id":583749,"name":"JC Bresnahan","orcid":null,"position":12,"is_corresponding":false},{"id":583750,"name":"MS Beattie","orcid":null,"position":13,"is_corresponding":false},{"id":296157,"name":"J. Russell Huie","orcid":"0000-0001-5594-4277","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:15:56.698770Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}