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Periodic Report Summary 3 - ATHERO-B-CELL (Targeting and exploiting B cell functions for treatment in cardiovascular disease)

Project Context and Objectives:
An experimental platform that permits the identification of mature B cell type(s) that either promote or prevent atherosclerosis and autoimmunity is lacking. Athero-B-Cell intends to identify differences in B cell effector subsets relevant to atherosclerosis and investigate how these differences can be used to develop new CVD therapeutics.
Athero-B-Cell aims to bridge the gap between the laboratory and the clinic by bringing together basic and clinical scientists with internationally recognised expertise in: the biology of B cell subsets (Mauri-UCL, Malin-KI, Patrone-UNIGE), omics of leukocytes in large-scale clinical studies (Hoefer-UMCU), humoral immunity in CVD (Nordin Fredrickson-ULund, Mach-UNIGeneva) and inflammatory signalling in atherosclerosis (Monaco-UOXF). Capitalising on available and emerging omics from previous EU-funded collaborations of the partners, Athero-B-Cell fosters a multidisciplinary environment where expertise from traditional chronic inflammatory diseases (UCL, and UNIGE) merges with CVD expertise.
The application of powerful “next generation” technologies will provide a step-up from the current state-of-the-art including: 1) bioinformatics-based pathway analyses from heterogeneous omics data sets; 2) high-resolution phenotyping of B cell subsets (mass cytometry, CyTOF); 3) genetically modified strains for the study of B cells in hypercholesterolemia and atherosclerosis; 4) targeting candidate genes in disease models with 3rd generation antisense drugs that have the potential to become therapeutics for clinical use.
The application of these technologies will enrich our understanding of B cell biology and the contribution of B cells to CVD and will help identify the patients that are mostly likely to benefit from them. This body of knowledge will be instrumental in the rational design of new therapies and vaccines to control CVD. Moreover, the Athero-B-Cell approach will develop a novel therapeutic pipeline of antisense drugs for translational use in CVD.

Specific Objectives:
1) To define targets to reduce activation of pathogenic B cells and antibodies in CVD
2) To identify enhancers of atheroprotective B regulatory cell populations and antibodies in CVD
3) To validate molecular and miRNA targets to modulate B cell behaviour in CVD with innovative locked nucleic acid (LNA) based antisense platforms.

Project Results:
In the third reporting period, the Athero-B-Cell Consortium has used the new research tools developed in the first 54 months (including a panel of antibodies to enable analysis and phenotyping of human B cell subsets in clinical cohorts and the generation of a new bioinformatics research tool) to generate further interesting results and publications. The work and accomplishments of the project so far are summarised below.

The key efforts of the WP1 Beneficiaries revolved around the execution of B cell specific –omics, phenotypic studies, and antibody production in blood and serum samples from CVD cohorts. B cells have been isolated from 295 samples from the AtheroExpress study and high-throughput transcriptomics analysis has been performed. Bioinformatic analysis has been applied to the data leading to the identification of differentially expressed genes in patients with versus without a follow-up cardiovascular event.

WP2 has made considerable progress with the development of tools of target selection. SME-based in silico platforms were needed to integrate the –omics data for selection of the pathways forming a specific B cell signature associated with CVD outcomes and B cell effector functions. A fully automated solution that can perform effective data collection, quality assurance, processing and normalisation, as well as comprehensive statistical and functional analysis has been developed and utilised on datasets of the consortium partners. Secondly, the ad-hoc panel of antibodies described in the first reporting period was used to interrogate the B cell compartment in cardiovascular disease. B cell content of 804 PBMC samples, collected as part of the prospective Malmo Diet and Cancer cardiovascular case control cohort, were phenotyped by flow cytometry. Initial analysis of the data has revealed interesting associations between specific B cell subsets.

In WP3 LNAs against targets involved in B cell activity have been generated. The LNAs generated against a model target in the previous reporting period that were found to display powerful knockdown of the target in vitro and in vivo and had safe pharmacology in mouse, have been applied to in vitro experiments and a murine model of cardiovascular disease. Moreover, we further studied how anti-ApoA1 auto-antibodies and anti-ApoB100 autoantibodies can affect the development of CVD in both animal models and human cohorts.

Significant progress has been made in WP4 towards the definition of the role of B cells in experimental models of atherosclerosis and also the generation of mouse models that specifically target B cells in hyperlipidemic mice. A novel mouse model, which will allow specific knockdown of Bregs in atherosclerosis as well as fate-mapping experiments that will provide insight into the atherosclerotic ontogeny of the Breg lineage, has been generated and initial experiments are ongoing. Further novel mouse models that will enable deeper understanding of the role of Bregs in disease are also being generated.

There have been extensive management activities in the project. We have organised a kick-off meeting in London (UK) (October 2013) and the annual meetings in Siena (Italy) (September 2014), Oxford (UK) (September 2015), Utrecht (Holland) (October 2016) and Copenhagen (Denmark) (October 2017). A workshop and annual meeting will take place in Athens (2018). These meetings were extremely valuable to our group and have enabled our consortium to keep pace with stringent self-imposed deadlines.
Also, the coordinator has had frequent teleconferences with the Scientific Manager, members of the Steering Committee and the Management Team to harmonise and coordinate the Athero-B-Cell efforts.

Dissemination of information about Athero-B-Cell is ongoing. A website has been established to provide public information ( on the Athero-B-Cell project and dissemination activities have effectively brought the study to public attention at an international level. The conceptual challenge of the Athero-B-Cell project has been discussed in numerous international meetings and numerous articles acknowledging Athero-B-Cell funding have been published. A brochure summarising project objectives and outcome has been produced for distribution to the scientific community.

Potential Impact:
The focus of Athero-B-Cell is to further evaluate and validate new therapeutically relevant targets that emerge from large-scale clinical trials for the primary and secondary prevention of CVD. The Consortium has pioneered research into the role that different B cell subsets play in the development and modulation of CVD. The opposing functions of subsets contained within the B cell population are a therapeutic opportunity never realized for CVD. All Athero-B-Cell project participants promote translational medicine, providing access to clinical material and the necessary environment to nurture basic and clinical science with necessary multidisciplinary infrastructure that is required to conduct first class research at an international level. The Athero-B-Cell Consortium will contribute to National and European Health by identifying molecular targets for the enhancement of endogenous regulatory responses and the abatement of the pro-atherogenic ones, ultimately generating new silencing tools for further drug discovery and development in CVD. The application of reverse translation approach to the development of 3rd generation antisense drugs for future clinical application will progress the way we tread CVD. This approach builds on the evaluation of existing and emerging omics datasets from ongoing clinical studies using novel bioinformatics, biological and translational approaches and it captures the opportunity for faster translation to the clinic by making full advantage of the innovative LNA platform for drug development.
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