Community Research and Development Information Service - CORDIS


CARTARDIS Report Summary

Project ID: 602936
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - CARTARDIS (Identification and validation of novel pharmaceutical drug targets for cardiovascular disease)

Project Context and Objectives:
The CarTarDis project (Cardiovascular Target Discovery) applies high quality expertise and resources within its multi-partner consortium to discover and validate novel therapeutic targets with a high level of clinical correlation to cardiovascular disease (CVD). The project adopted a strong pharmaceutical workflow in which human cardiovascular cohorts, clinical biobanks, molecular analysis methodologies and preclinical models play a key role.
The CarTarDis workflow for discovery of novel CVD targets comprises several distinct phases. First, available and emerging molecular data from literature and our own prorprietary sources have been mined for statistical association with cardiovascular disease phenotypes, with a preference for genetic associations. Pharma process-driven filters were designed including drugability, novelty, biological function, mechanism of action, assayability and freedom to operate. Following selection and prioritisation of preselected potential CVD drug targets by these filters, candidate targets are being validated by two parallel approaches. One validation approach is based on analysis of two unique high quality human cardiovascular biobanks that provide additional rationale of the role of candidate targets in human cardiovascular disease. Samples have been evaluated using several high resolution molecular analysis methods that allowed a spatial expression analysis of the target and target-related pathways on RNA, protein and small molecule level. The second, parallel, validation approach generated and used in vitro and in vivo preclinical models using which the mechanism of action and role of candidate targets in cardiovascular processes can be studied. In combination, this workflow provides highly informative data regarding validation of candidate targets in cardiovascular disease to maximize success in clinical development in later stages.

The CarTarDis project started 1 October 2013 and is running according to plan. The consortium partners have been interacting intensely since the start, initially to familiarize each partner with the expertise, capabilities and ambitions in the field of CVD research. Soon thereafter, the consortium focused on operationalizing the workflows and developing relevant methods within the various work packages. In parallel, multidisciplinary teams formed to execute validation experiments on specific targets. Overall, four main activities have been performed:
1. Definition of the selection and prioritization procedure and criteria for candidate drugable CVD targets.
2. Comprehensive collection of candidate targets and the subsequent selection and prioritisation.
3. Development of in vitro and in vivo CVD models for target validation.
4. Development of molecular analysis methods to characterize human CVD biobank samples.

Project Results:
1. Definition of the selection and prioritization procedure and criteria for candidate drugable CVD targets.
We adopted the 5R strategy as proposed by AstraZeneca, providing an evidence-based best practice in pharmaceutical drug development. The 5R strategy outlines the assessment of drugs at various levels: Right Target, Right Patients, Right Tissue, Right Safety, Right Commercial Potential of which the first two applied best to our project as these relate to properties of the drug targets themselves. We defined various levels of assessment of our portfolio of candidate CVD drug targets: Drugability, Novelty, Genetic/omic evidence, Feasibility, Pathways, including weights of each of these criteria. The review and prioritization of our candidate targets was done through a combination of automatic scoring and expert reviews.

2. Comprehensive collection of candidate targets and the subsequent selection and prioritisation.
Our multidimensional evaluation of potential targets yielded 380 pre-selected drug targets from public and proprietary data sources. We built a database containing various levels of information for each target which was grouped into the aforementioned categories of relevance and subjected to the automated and expert reviewing. The proprietary data in the database were protected with a password and an IP restriction. The target reviewing process yielded 7 potential CVD drug targets with the highest priority, with different mechanisms of action, novelty and risks. All public and proprietary knowledge on these targets was being collected and shared with consortium members through a common on line website. Target validation plans were drafted with input from all relevant partners to steer and monitor subsequent validation work.

3. Development of in vitro and in vivo CVD models for target validation.
Based on the expertise and capabilities of the partners, we defined the most suited models and strategies for mechanistic validation of the selected CVD drug targets. In vivo models included novel transgenic mouse lines using innovative construction strategies to facilitate tight regulation of transcriptional control for mechanistic validation of selected targets. We are combining these novel models with the well characterized ApoE3Leiden mouse model but also with a PCSK9 viral vector to speed up the generation of the mouse models. In addition, we are generating knock-out/knock-in models aiming at plaque rupture models, which are highly needed by pharmaceutical companies to evaluate drugs whose mode of action involves stabilization of plaques. In vitro cellular models mimicking parts of the CVD pathophysiology were developed including optimized cultures of relevant cell lines and 3D culture primary endothelial cell cultures. A preclinical mouse biobank was set up that mirrors the human biobanks and will enable cross-species molecular analysis of the selected CVD targets and their pathways.

4. Development of molecular analysis methods to characterize human CVD biobank samples.
The two unique human biobanks in the CarTarDis consortium contain precious biobanked human material from CVD patients in all stages of disease. Analysis of those samples will provide evidence for clinical relevance as it will reveal expression of the selected targets and the activity of the associated pathways in highly relevant CVD material. The partners set up a multi-partner sample exchange program where the same CVD sample is analysed by multiple partners with their specific molecular staining methodologies. New methods were developed to visualize the presence of target-specific RNA, protein and lipid molecules to support each of the target validation projects. Molecular information of the selected targets is being used to define the best suited biomarkers to assess the activities of the target-specific pathways as part of the target validation activities.

Potential Impact:
The CarTarDis project is generating a wealth of scientific knowledge on pathways, targets and biomarkers clinically derailed in CVD that contribute to initiation and progress of CVD. Moreover, the current progress in the project indicates that several useful tools to support CVD drug discovery will become available. These include expanded clinically relevant CVD tissue biobanks to reveal more information on mechanisms of disease, cutting edge molecular assays to accurately monitor proteins, RNA and metabolites in such biosamples, and in vitro and in vivo mechanistic and efficacy models to enable the monitoring of the biological function of CVD targets. In addition, the efficient drug target selection and prioritization process developed by the CarTarDis consortium can be an example of a multi-partner EU-wide virtual pharma approach that may benefit drug development activities in other disease areas as well, as also indicated by our External Advisory Board.
The knowledge and potential products generated in the CarTarDis project will significantly contribute to the growth and market position of the profit partners and especially the SMEs in this project, being highly specialized innovative service providers. Their participation in this pharmaceutical project will increase their experience in critical steps in the target discovery process, facilitating new partnering and formation of a more profitable and competitive position in the field.
The high quality validated drug targets that will be produced by the CarTarDis consortium are expected to be of interest to pharmaceutical industries, whereby the CarTarDis SMEs will be logical partners for co-development using the developed in vitro and in vivo models and molecular analysis methodologies to support preclinical and clinical development.
Finally, we actively disseminate the expertise available within and acquired by the CarTarDis consortium. As part of this, we initiated the organisation of the joint EU FP7 CVD research consortium meeting September 2016 whereby the CarTarDis, Cvgenes@target and TransCard consortia got together and exchanged information on insights into mechanisms of cardiovascular disease and each others expertise. It provided a good building block for future collaborations within Europe, fulfilling our ambitions to contribute to a stronger cardiovascular research network in Europe.

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