Genes and genes combinations predictive of early response or non response of subjects suffering from inflammatory disease to cytokine targeting drugs (CYTD)

A technology for cytokines and inflammatory diseases, applied in drug combinations, skin diseases, bone diseases, etc., can solve problems such as false positives

Inactive Publication Date: 2013-02-06
TC LAND EXPRESSION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as with all studies of this type, using microarray technology to simultaneously measure thousands of genes in a relatively small patient population runs the risk of over-fitting the data, leading to false positive results
Furthermore, the single-center nature of these studies may limit the relevance of the identified genes to a broader and more demographically diverse population

Method used

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  • Genes and genes combinations predictive of early response or non response of subjects suffering from inflammatory disease to cytokine targeting drugs (CYTD)
  • Genes and genes combinations predictive of early response or non response of subjects suffering from inflammatory disease to cytokine targeting drugs (CYTD)
  • Genes and genes combinations predictive of early response or non response of subjects suffering from inflammatory disease to cytokine targeting drugs (CYTD)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0207] Example 1: Meta-analysis of two datasets (Bienkowska et al. (9) and Julia et al. (8))

[0208] Materials and methods

[0209] In this example, the materials and methods used in subsequent Examples 1-3 are described.

[0210] Data Validation and Data Extraction : Studies were selected on the basis that they had been performed in biologic-naïve RA patients who initiated therapy with infliximab and had measurements of their response to treatment obtained at 14 or 22 weeks. Large-scale gene expression information needs to be obtained at baseline (before treatment). Following the procedure described by Ramasamy et al. (10), we identified four studies that met our study criteria: Lequerré et al. (6), Sekiguchi et al. (7), Bienkowska et al. (9) and Julià et al. (8). Expression data, phenotype and annotation data were all downloaded from GEO (GSE3592, GSE8350, GSE12051 and GSE15258, respectively).

[0211] All four studies identified "gene expression signatures of respon...

Embodiment 2

[0251] Example 2: Meta-analysis of three datasets (Bienkowska et al., Julia et al. and Sekiguchi et al)

[0252] A second meta-analysis was performed after merging the Sekiguchi et al. dataset. This greatly reduces the number of genes tested, bringing it down to 290. Keeping the same threshold (2.5) as the previous test statistic, only three of the 61 genes described (see Example 1) were significant: IL2RB, S100A9 and CASP5. However, these genes broadened the prediction of infliximab treatment to 22 weeks follow-up. In addition to the relationship between IL2RB and S100A9 and RA pathophysiology (see above), the CASP5 gene is also of relative significance in this autoimmune disease.

[0253] CASP5

[0254] The CASP5 gene encodes caspase 5, which proteolytically cleaves other proteins at aspartic acid residues. It is an inflammatory caspase that plays an important role in the immune system (27) and in complex processes of apoptosis (28).

[0255] Abnormally reduced or i...

Embodiment 3

[0256] Example 3: Meta-analysis of four datasets (Bienkowska et al., Julia et al., Sekiguchi et al. and Lequerré et al.)

[0257] Further adding the data by Lequerré et al., and thus resulting in a total of 103 samples analyzed, of the 179 genes identified, only two of the 61 genes previously described (see Example 1) were found in non-responders Significantly increased in: MAPK14 and S100A9 ( figure 2 ). The combination of these two genes was thus able to predict response to infliximab treatment at week 14 or week 22 on biological samples (whole blood or PBMC).

[0258] MAPK14

[0259] The MAPK14 gene encodes mitogen-activated protein kinase 14, a member of the MAP kinase family. MAP kinases function as integration points for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcriptional regulation, and development. The MAP kinase pathway inter alia affects the biosynthesis of the pro-infla...

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Abstract

This invention refers to the field of human medicine and specifically to the diagnosis / prognosis of the responsiveness to a cytokine targeting drug (CyTD) treatment of a subject suffering from an inflammatory disease. More precisely, the present invention concerns a method for the in vitrodiagnosis / prognosis of a CyTD responsive or non-responsive phenotype, comprising: (a) determining from a subject biological sample an expression profile comprising the gene MAPK14; or the genes MAPK14 and S100A9; or the genes MAPK14 and GNLY; or the 6 genes of Table 2, or the gene S100A9; or the genes S100A9, IL2RB, and CASP5; or the genes S100A9, IL2RB, KLRK1, HCK, and GNLY; or the genes S100A9, IL2RB, KLRK1, HCK, GNLY, CTSZ, ARF5, and UTP14C, or Equivalent Expression Profile of anyone of the expression profiles of (i) and (ii), and optionally one or more housekeeping gene(s), (b) comparing the obtained expression profile with at least one reference expression profile, and (c) determining the responsive or non-responsive phenotype from said comparison. The present invention also relates to kits and nucleic acid microarrays for performing said method. The present invention also relates to methods of treatment of inflammatory disease-suffering patients.

Description

Background technique [0001] Cytokine targeting drugs such as TNFα blockers (hereinafter referred to as "TBA") are increasingly used in the treatment of various inflammatory diseases. The first indications for which this TBA was approved were rheumatoid arthritis and Crohn's disease. Rheumatoid arthritis (RA) is a chronic, progressive, debilitating autoimmune disease of largely unknown etiology, affecting approximately 1% of the population (1). RA is characterized by chronic inflammation of the synovium, which ultimately leads to joint damage, pain and disability (2). The clinical spectrum of RA is heterogeneous, ranging from mild to severe, with differences in the secondary organ systems involved. Differences in response rates to current treatments further illustrate disease heterogeneity. First-line treatment is usually started with so-called disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX). About 30% of patients show suboptimal response or canno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q1/6883C12Q2600/158C12Q2600/106C12Q1/6809C12Q1/6876A61P1/04A61P17/06A61P19/02A61P25/00A61P29/00A61P37/02A61P9/00
Inventor A·赛维诺O·R·波帕-尼察C·布劳德
Owner TC LAND EXPRESSION
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