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Projects / Programmes source: ARIS

Molecular genetic biomarkers and mechanisms of unresponsiveness to biological therapy anti-TNF in patients with chronic immune diseases

Research activity

Code Science Field Subfield
3.01.00  Medical sciences  Microbiology and immunology   

Code Science Field
B220  Biomedical sciences  Genetics, cytogenetics 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
genetics, phramacogenomics, chronic immune diseases, biological drugs, complex diseases
Evaluation (rules)
source: COBISS
Researchers (33)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  33666  PhD Vojko Berce  Microbiology and immunology  Researcher  2018 - 2021  228 
2.  25434  PhD Urban Bren  Chemistry  Researcher  2018 - 2021  367 
3.  29835  PhD Tomaž Budefeld  Microbiology and immunology  Researcher  2020 - 2021  92 
4.  36818  PhD Helena Sabina Čelešnik  Biochemistry and molecular biology  Researcher  2018 - 2021  61 
5.  53354  Petra Dekleva    Technical associate  2020 
6.  19125  PhD Jernej Dolinšek  Metabolic and hormonal disorders  Researcher  2018 - 2021  605 
7.  28477  PhD Matjaž Finšgar  Chemistry  Researcher  2018 - 2021  402 
8.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2018 - 2021  187 
9.  26010  PhD Boris Gole  Biochemistry and molecular biology  Researcher  2018 - 2021  75 
10.  33268  PhD Mario Gorenjak  Biochemistry and molecular biology  Researcher  2018 - 2021  164 
11.  34478  PhD Larisa Goričan  Microbiology and immunology  Researcher  2018 - 2021  35 
12.  20420  PhD Lidija Gradišnik  Neurobiology  Researcher  2018 - 2021  293 
13.  23563  PhD Iva Hafner Bratkovič  Neurobiology  Researcher  2018 - 2021  212 
14.  15751  PhD Radovan Hojs  Metabolic and hormonal disorders  Researcher  2018 - 2021  799 
15.  18036  PhD Tanja Hojs-Fabjan  Neurobiology  Researcher  2018 - 2021  247 
16.  23215  PhD Evgenija Homšak  Microbiology and immunology  Researcher  2018 - 2021  158 
17.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Researcher  2018 - 2021  1,192 
18.  39240  PhD Gregor Jezernik  Microbiology and immunology  Researcher  2018 - 2021  39 
19.  28039  PhD Silvo Koder  Pharmacy  Researcher  2018 - 2021  43 
20.  02053  PhD Ivan Krajnc  Microbiology and immunology  Researcher  2018 - 2021  615 
21.  15501  PhD Peter Krajnc  Chemistry  Researcher  2018 - 2021  488 
22.  21426  PhD Mateja Manček Keber  Pharmacy  Researcher  2018 - 2021  159 
23.  15998  PhD Nataša Marčun Varda  Cardiovascular system  Researcher  2018 - 2021  473 
24.  30850  PhD Uroš Maver  Medical sciences  Researcher  2018 - 2021  454 
25.  02057  PhD Dušanka Mičetić-Turk  Human reproduction  Researcher  2018 - 2021  1,116 
26.  15750  PhD Artur Pahor  Microbiology and immunology  Researcher  2018 - 2021  313 
27.  20129  PhD Dušica Pahor  Metabolic and hormonal disorders  Researcher  2018 - 2021  777 
28.  16340  PhD Uroš Potočnik  Microbiology and immunology  Head  2018 - 2021  631 
29.  28417  PhD Katja Repnik  Microbiology and immunology  Researcher  2018 - 2019  132 
30.  53355  PhD Erik Rihtar  Biochemistry and molecular biology  Junior researcher  2019 - 2021 
31.  18035  PhD Pavel Skok  Metabolic and hormonal disorders  Researcher  2018 - 2021  676 
32.  32132  PhD Andraž Stožer  Metabolic and hormonal disorders  Researcher  2018 - 2021  428 
33.  07561  PhD Boris Turk  Biochemistry and molecular biology  Researcher  2018 - 2021  1,037 
Organisations (5)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  2334  University of Maribor, Faculty of Medicine  Maribor  5089638048  16,582 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,293 
3.  0106  Jožef Stefan Institute  Ljubljana  5051606000  91,017 
4.  0334  University Medical Centre Maribor  Maribor  5054150000  22,867 
5.  0794  University of Maribor, Faculty of Chemistry and Chemical Engineering  Maribor  5089638012  13,076 
Abstract
The proinflammatory cytokine tumour necrosis factor-α (TNF) plays a dominant role in pathogenesis of chronic immune diseases, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). Biological drugs capable of blocking it, i.e. etanercept (ETN), infliximab (IFX) and adalimumab (ADA), became leading treatment of several autoimmune conditions including RA and CD in most severe cases. However, from 30%-50% (long-term response) of severe CD and RA cases do not respond to anti-TNF therapy. The causes of this non-response are poorly understood. Clinical predictors and serological biomarkers were associated with anti-TNF response but are not accurate enough for use in clinical practise. Recently, pharmacogenetics and pharmacogenomic studies proved that single nucleotide polymorphisms (SNPs) and gene expression profiles measured before treatment could predict anti-TNF treatment response. Our group discovered that genes in the autophagy pathway, including ATG16L1 and ATG5, are associated with ADA response in CD patients. For efficient pharmacogenomic studies in anti-TNF therapy, a good insight into the genetic architecture of chronic immune diseases is essential. Together with our partners at the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) we recently performed a Genome Wide Association Study (GWAs) using specialized custom designed genotyping microarray Immunochip (iCHIP) in 75,000 IBD patients and controls. We discovered 163 IBD associated loci, providing the best description of genetic architecture of IBD and related chronic immune diseases so far (Nature, 2012;491(7422):119-24) and discover most important disease causing genes (Nature, 2017; 547(7662):173-178)) The aim of our proposed study is to describe the molecular mechanisms contributing to the anti-TNF therapy nonresponse in patients with CD and RA, and to identify molecular genetic markers that could predict anti-TNF response. These could be used for personalized/precision medicine. Integration of genetic (NGS, genotyping), gene expression (RNAseq), proteomic, epigenetic (DNA modifications) and gene regulation (noncoding RNA profiling, splice variants) data with bioinformatic tools (gene ontology- GO) will ensure identification and description of biological pathways important in anti-TNF treatment response. Our study is fully feasible, as we have already developed a comprehensive biobank that includes one of the world's largest collections of combined DNA/RNA/protein samples for chronic immune diseases (600 IBD, 300 RA). Part of our biobank represent RNA samples from the subgroup of CD patients that are refractory to standard treatment, collected before and during ADA treatment (weeks 4, 12, 20, 30). Our biobank is unique worldwide and thus holds excellent promise for providing new discoveries. In addition, we also have accurate clinical data of the treatment response, as measured by the IBDQ index and CRP for IBD patients and DAS28 index for RA patients. Our biobank will enable gene expression profiling in patients with the severe form of disease receiving biological therapy and monitoring of the changes in these profiles during anti-TNF therapy in non-responders. Together, our studies will give a deep insight into molecular biological pathways important for disease progression, recovery and developing resistance to anti-TNF therapy. Interesting new findings are expected from the comparison between gene expression profiles obtained from patients on anti-TNF therapy representing TNF inhibition in vivo and RNA samples obtained from treated cell cultures and cell lines, representing inhibition in vitro. According to our and other preliminary studies, autophagy and Toll-like receptors (TLRs) signalling, seem to be the best candidate molecular pathways associated with anti-TNF treatment response and will be initially the focus of our molecular pathway functional studies.
Significance for science
Original scientific contribution is ensured: As the first complete transcriptome analysis using NGS (RNA-seq) before and during anti-TNF treatment, this study will provide new expression profiles that will efficiently predict treatment outcomes in CD and RA as part of personalized therapy. Expression profiles, combined with genetic biomarker analyses, proteomics, epigenetic studies and non-coding regulatory RNA profiling will be used to identify potential new biomarkers of response to anti-TNF drugs. Patients could suffer from less adverse side effects if therapy is personalized based on molecular and genetic biomarkers. Interesting new findings are expected from the comparison between gene expression profiles obtained from patients on anti-TNF therapy representing TNF inhibition in vivo and RNA samples obtained from treated cell cultures and cell lines, representing inhibition in vitro. This comparison will help to distinguish gene expression regulation that is caused primarily by inhibition of TNF (in vitro study) from the regulation that is caused in vivo by other more complex (multiple) downstream patterns. Furthermore, in vitro analyses will enable detailed elucidation of molecular pathways that are implicated in the responsiveness of IBD patients to anti-TNF treatment. The progress beyond the state-of-the-art and scientific impact is ensured: Identification of biological and signalling pathways that change during anti-TNF treatment in responders but do not show the same trend in non-responders will provide new molecular targets that will enhance development of novel biological drugs. Identification of new parameters with clinical importance (e.g. transcript variants, SNPs) will facilitate functional studies and development of biomarkers and predictive models for precision medicine. Personalized therapy represents an optimal approach to treatment: as precisely fitted therapy can be applied from the beginning of treatment, patients could suffer from less adverse side effects and overall treatment costs can be reduced.    Obtained results will expose and outline new research areas. For example, mapping of functional regulatory polymorphisms will help better understand mechanisms of gene expression regulation. Elucidating the genes and proteins affected by SNPs will help understand biological pathways involved in disease pathogenesis and identify molecular targets for new biological drugs. Results of this project will enhance development of biological drugs. Prof. Potočnik´s group is member of consortium that has already developed project “Isolation procedures in modern production of biological drugs”, and consist of partners from industry, Brinox .d.o.o., Labena d.o.o., EVG. d.o.o., Cleangrad d.o.o. and research institutions Faculty of Medicine, UM, Institute Jožef Stefan and Faculty for Pharmacy, UL. The consortium contract has already been signed, for a total of:  2,1 milion eur; MF UM: 230, 000, 00 eur.
Significance for the country
Original scientific contribution is ensured: As the first complete transcriptome analysis using NGS (RNA-seq) before and during anti-TNF treatment, this study will provide new expression profiles that will efficiently predict treatment outcomes in CD and RA as part of personalized therapy. Expression profiles, combined with genetic biomarker analyses, proteomics, epigenetic studies and non-coding regulatory RNA profiling will be used to identify potential new biomarkers of response to anti-TNF drugs. Patients could suffer from less adverse side effects if therapy is personalized based on molecular and genetic biomarkers. Interesting new findings are expected from the comparison between gene expression profiles obtained from patients on anti-TNF therapy representing TNF inhibition in vivo and RNA samples obtained from treated cell cultures and cell lines, representing inhibition in vitro. This comparison will help to distinguish gene expression regulation that is caused primarily by inhibition of TNF (in vitro study) from the regulation that is caused in vivo by other more complex (multiple) downstream patterns. Furthermore, in vitro analyses will enable detailed elucidation of molecular pathways that are implicated in the responsiveness of IBD patients to anti-TNF treatment. The progress beyond the state-of-the-art and scientific impact is ensured: Identification of biological and signalling pathways that change during anti-TNF treatment in responders but do not show the same trend in non-responders will provide new molecular targets that will enhance development of novel biological drugs. Identification of new parameters with clinical importance (e.g. transcript variants, SNPs) will facilitate functional studies and development of biomarkers and predictive models for precision medicine. Personalized therapy represents an optimal approach to treatment: as precisely fitted therapy can be applied from the beginning of treatment, patients could suffer from less adverse side effects and overall treatment costs can be reduced.    Obtained results will expose and outline new research areas. For example, mapping of functional regulatory polymorphisms will help better understand mechanisms of gene expression regulation. Elucidating the genes and proteins affected by SNPs will help understand biological pathways involved in disease pathogenesis and identify molecular targets for new biological drugs. Results of this project will enhance development of biological drugs. Prof. Potočnik´s group is member of consortium that has already developed project “Isolation procedures in modern production of biological drugs”, and consist of partners from industry, Brinox .d.o.o., Labena d.o.o., EVG. d.o.o., Cleangrad d.o.o. and research institutions Faculty of Medicine, UM, Institute Jožef Stefan and Faculty for Pharmacy, UL. The consortium contract has already been signed, for a total of:  2,1 milion eur; MF UM: 230, 000, 00 eur.
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