 An integrative transcriptome analysis framework for drug efficacy and similarity reveals drug-specific signatures of anti-TNF treatment in a mouse model of inflammatory polyarthritisNiki Karagianni, Ksanthi Kranidioti, Nikolaos Fikas, Maria Tsochatzidou, Panagiotis Chouvardas, Maria C Denis, George Kollias and Christoforos Nikolaou PLOS Computational Biology, 2019, vol. 15, issue 5, 1-25 Abstract: Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn’s Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcriptomics profiling of four different anti-TNF biologics upon treatment of the established hTNFTg (Tg197) mouse model of spontaneous inflammatory polyarthritis. We implement a series of computational analyses that include clustering of differentially expressed genes, functional analysis and random forest classification. Taking advantage of our detailed sample structure, we devise metrics of treatment efficiency that take into account changes in gene expression compared to both the healthy and the diseased state. Our results suggest considerable variability in the capacity of different biologics to modulate gene expression that can be attributed to treatment-specific functional pathways and differential preferences to restore over- or under-expressed genes. Early intervention appears to manage inflammation in a more efficient way but is accompanied by increased effects on a number of genes that are seemingly unrelated to the disease. Administration at an early stage is also lacking in capacity to restore healthy expression levels of under-expressed genes. We record quantifiable differences among anti-TNF biologics in their efficiency to modulate over-expressed genes related to immune and inflammatory pathways. More importantly, we find a subset of the tested substances to have quantitative advantages in addressing deregulation of under-expressed genes involved in pathways related to known RA comorbidities. Our study shows the potential of transcriptomic analyses to identify comprehensive and distinct treatment-specific gene signatures combining disease-related and unrelated genes and proposes a generalized framework for the assessment of drug efficacy, the search of biosimilars and the evaluation of the efficacy of TNF small molecule inhibitors.Author summary: A number of anti-TNF drugs are being used in the treatment of inflammatory autoimmune diseases, such as Rheumatoid Arthritis and Crohn’s Disease. Despite their wide use there has been, to date, no detailed analysis of their effect on the affected tissues at a transcriptome level. In this work we applied four different anti-TNF drugs on an established mouse model of inflammatory polyarthritis and collected a large number of independent biological replicates from the synovial tissue of healthy, diseased and treated animals. We then applied a series of bioinformatics analyses in order to define the sets of genes, biological pathways and functions that are affected in the diseased animals and modulated by each of the different treatments. Our dataset allowed us to focus on previously overlooked aspects of gene regulation. We found that the majority of differentially expressed genes in disease are under-expressed and that they are also associated with functions related to Rheumatoid Arthritis comorbidities such as cardiovascular disease. We were also able to define gene and pathway subsets that are not changed in the disease but are, nonetheless, altered under various treatments and to use these subsets in drug classification and assessment. Through the application of machine learning approaches we created quantitative efficiency profiles for the tested drugs, which showed some to be more efficiently addressing changes in the inflammatory pathways, while others being quantitatively superior in restoring gene expression changes associated to disease comorbidities. We thus, propose a concise computational pipeline that may be used in the assessment of drug efficacy and biosimilarity and which may form the basis of evaluation protocols for small molecule TNF inhibitors. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006933 DOI: 10.1371/journal.pcbi.1006933 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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