Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


RISKYCAD Berichtzusammenfassung

Project ID: 305739
Gefördert unter: FP7-HEALTH
Land: Greece

Periodic Report Summary 2 - RISKYCAD (Personalized diagnostics and treatment of high risk coronary artery disease patients.)

Project Context and Objectives:
The general aims of RiskyCAD are 1) to identify lipidomic and miRNA biomarkers for high risk coronary atherosclerosis and use them alone or in combination with standard risk models to improve the identification of patients in high risk for myocardial infarction or death, 2) to unwind mechanistic links between disease risk and biomarkers, and investigate rational therapeutic approaches, 3) to develop novel diagnostic and therapeutic strategies based on patient stratification and ‘drug repositioning’.

Project Results:
During these first 36 months, significant progress has been realized. In WP1, the LURIC cohort has been genotyped using the Illumina exome array for rare variants. First analyses have been performed and data have also been submitted to international meta-analysis consortia. The analysis of circulating miRNAs in 1500 samples of the LURIC cohort has also been completed. Lipidomic analyses have further revealed an association of specific fatty acid subspecies with the prognosis of patients with and without coronary artery disease which is being explored further. New risk stratification algorithm for stable coronary artery disease termed BIO-VILCAD-SCORE and COROPREDICT have been developed. In WP2, the recruitment of high and low risk CAD patients, as well as healthy controls, has finished. Following comparison and optimization of methodologies for hepatic differentiation, hepatocyte-like cells (HLCs) have been obtained and initially characterized. Further characterization of HLCs continues as part of WP3 and involves lipidomics analyses and miRNA profiling studies.
In WP4, the development of new mouse models of CAD has progressed. Several strategies have been selected including the generation of floxed SR-BI mice for the conditional regulated deletion of the SR-BI gene, and knock-in mice for the conditional expression of CHOP or DTR (for triggering necrotic cell death) in lesional macrophages. The generation of these mice is almost complete. These models will be characterized, crossed with relevant transgenic mice and transferred to the Apoe-/- background. As an additional approach, mouse models of coronary atherosclerosis and plaque vulnerability based on perturbed shear stress have been established and characterized in detail.
Progress has also been realized in WP5. Various formulations have been screened and methodologies have been developed for optimal transfection efficacy of antisense DNA and siRNA oligonucleotides to cultured hepatocytes and epithelial origin cells. A comparison between free (unformulated) and liposome-formulated antisense oligonucleotide (ASO) systemic administration has also been performed. In parallel, alternative approaches to evaluate novel targets of CAD have been pursued based in the use of apolipoprotein (apo)A-I and E or IFN lambda receptor 1 and apoE-deficient mice.
In WP6, analytical platforms for the quantification of molecular species from a wide spectrum of lipid classes have been set up. These were used to analyze 218 stringently matched triplets from the COROGENE study, with each triplet containing a patient with an unstable CAD leading to CV death, a patient with stable CAD (stenosis 20%-50%) and a control subject (stenosis<20%). Ceramide biomarker candidates identified in the Corogene study and reconfirming the LURIC study’s data were validated in two additional cohorts, BECAC and SPUM-ACS. Results from all cohorts were analysed and associations between a variety of potential biomarkers and CVD death were evaluated in order to select the clinically most important biomarkers to gauge outcome event risk in CAD patients. A targeted analytical platform with high precision and accuracy is currently being developed for commercial use.
Finally, in WP7 drug repositioning through the use of the Clinical Outcomes Search Space (COSS™) platform has progressed. ‘Lead’ compounds have been identified and will be tested in preclinical mouse models of coronary atherosclerosis and reprogrammed disease-relevant cells from high risk CAD patients. Tranilast, an off-patent anti-allergic drug that exhibits multiple anti-inflammatory and immunomodulatory actions, has also been evaluated for repositioning in CAD with very encouraging results. In Apoe-/- mice, tranilast was shown to inhibit macrophage accumulation and neointima formation induced by perivascular collar placement onto the murine carotid artery.
The execution of the project has been smooth through the use of an effective management structure taking care of the various administrative, financial, dissemination and intellectual property (I.P.) issues that occasionally arise.

Potential Impact:
Overall, the progress towards the project’s objectives has been satisfactory and is expected to move forward further during the 3rd project reporting period. It is anticipated that in the next 18 months the analysis of new biomarkers (including lipidomic, miRNA and other biomarkers) for high risk CAD patients from the LURIC cohort will be completed and new molecules identified. Some of these will have been reconfirmed in other cohorts as well. Differentiation of iPS cells from CAD patients to endothelial cells and/or macrophages (in addition to hepatocytes) will have been achieved and cells will be investigated for molecular processes and pathways that are dysregulated in high risk individuals. The generation of new mouse models of CAD will have finished, and their characterization will have progressed. Eviddence for their ability to replicate features of coronary atherosclerosis and plaque vulnerability will be available. New antisense oligonucleotides for selected disease targets will be investigated and lead drugs repurposed for CAD identified. Finally, validation of new lipid biomarkers will be replicated in the COROGENE study. Efforts to develop a diagnostic test for routine clinical application for risk prediction, as well as prediction algorithms, will be intensified.

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Scientific Research
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