Project

Project

RiskyCAD has been set with the aim to identify high risk asymptomatic patients and improve primary prevention of CAD by developing novel therapeutics and tailoring treatment to best match the individual patient’s profile.

It has been inspired from our earlier findings using high throughput lipidomics in >1.000 patients of the LURIC cohort of CAD patients (ongoing trial) that certain molecular lipid species such as distinct phospholipids and sphingolipids, found at low concentration, are much better predictors of clinical outcome events than traditional risk factors such as LDL-cholesterol (LDL-C) or HDL-cholesterol. This can be attributed to single lipids rather than lipidomic profiles, suggesting that the identification of individual biomarkers of high prognostic value is possible. Therefore, new omics technologies favoured by unprecedented level of detail and sensitivity by comparison to classical analytical approaches offer a unique opportunity for identifying novel biomarkers and revisiting longstanding questions on risk stratification of asymptomatic individuals.

To build on these earlier observations for patient stratification, identify novel biomarkers for CAD, and develop new diagnostic tools and ‘personalized’ therapeutic strategies, RiskyCAD partners have agreed on the following objectives below:

1. To identify lipidomic and miRNA biomarkers for asymptomatic patients in high risk of coronary events, myocardial infarction or death, and use them alone or in combination with standard risk models to improve the classification of CAD patients.
2. To unwind the 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’

To achieve these aims, detailed functional and translational studies will be carried out in order to illuminate the involved metabolic and molecular signalling pathways conferring high or low risk of CAD. The experimental studies will take advantage of the latest developments in iPS cell technology, lipidomic platforms, miRNA biomarker discovery tools, and targeted gene silencing in animal models using RNAi oligonucleotides and novel liposomal carriers. We will look into new biomarkers for asymptomatic patients in high risk of CAD using some of the finest cohorts (WP1), identify new molecules and develop new diagnostic kits that will be further validated in additional cohorts (WP6). We will also generate reprogrammed iPS cell based human models for the study of metabolic aberrations in selected individual vulnerable CAD patients (WP2). We will identify defects, e.g. in liver lipid metabolism, in high risk CAD patients (WP3) and test targeted treatments in preclinical animal models to provide proof-of-concept level evidence for new drug development (WP5). Both traditional and new animal models of coronary atherosclerosis constructed during the project will be used (WP4). A strong emphasis will be given to an improved risk assessment at individual patient level. As our approach is based on well characterized patients and phenotypes, we will generate clinically applicable stratification methods that will allow targeted treatment and patient enrichment for clinical trials (WP1). Unique predictive modelling and Drug Repositioning platforms will be used to select drugs or drug combinations that will best match the patient’s biomarker profile (WP7). At the end of the project, novel diagnostic tests will be subjected to the qualification process at EMA and FDA, while new drug or drug combinations will be considered for further clinical development (Figure). The final (translational) outcomes of this project will be: (i) a set of distinct biomarker test(s) for asymptomatic patients in high risk of CAD that can be ordered both by primary care physicians and specialized cardiologists from routine clinical laboratories; (ii) new CAD risk estimation models; (iii) a set of repositioned drugs ready to be exploited further for the optimal treatment of patients in high risk of CAD.