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Athero-Flux Report Summary

Project ID: 602222
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 2 - ATHERO-FLUX (Targeting novel lipid pathways for treatment of cardiovascular disease)

Project Context and Objectives:
Cardiovascular disease (CVD) causes much of the disease burden in Europe, claiming each year 4.3 million lives in Europe, 2.0 million in the EU (European Heart Network; The main forms of CVD are coronary artery disease (CAD) and stroke. CAD by itself is the single most common cause of death in Europe: accounting for 1.8 million deaths in Europe and 681,000 deaths in the EU per year (European Heart Network;
Lipid lowering has significantly reduced CVD mortality in EU. However, the aim to abolish CVD in EU is far from achieved and attempts to improve on the benefits of statins with new agents have not yet delivered new therapeutics. The Consortium Athero-Flux builds on large-scale lipidomics data showing that specific sphingolipids (SLs) with specific acyl chain lengths are better predictors of CV outcome than traditional risk factors such as low-density lipoprotein-cholesterol.

SLs are implicated in significant biological activities including cell survival, inflammation, and metabolic diseases. Moreover, their levels in metabolic diseases are modulated by previously unrecognized factors such as the gut microflora. Thus, we hypothesize that by controlling SL metabolism a better primary and secondary prevention of CVD events than with statins alone can be achieved.
Athero-Flux aims to identify, characterise and validate novel therapeutic targets for CVD by dissecting the biosynthesis and pro-atherogenic potential of specific molecular species of SLs identified by lipidomics as strong predictors of CV risk in large-scale clinical studies.

Athero-Flux builds on cutting-edge SME-led biotechnological tools including: a) high-throughput lipidomic platforms that allow the study of kinetics of lipid metabolism at the molecular lipid level including the new stable isotope labelling technique (Flux); b) whole genome RNA interference screening tools that will allow to identify the regulators of the production of SL and the mediators of their biological effect; c) unique locked nucleotide antagonist platforms that have been successfully used clinically in more that 300 patients worldwide. Moreover, it involves Academic partners with top expertise in atherosclerosis, SL metabolism, and gut microflora to validate targets in the SL metabolism. The identification and the validation of the best targets to abate SL metabolism though a combination of SME-based leading technology and academia modeling has a strong potential for development of new lipid lowering therapeutics to abate previously unrecognized risk factors for CVD.

Project Results:
Significant progress has been made in the second reporting period. Key achievements include: 1) Success in the derivation of induced pluripotent stem cell (iPSC) derived hepatocytes for ceramide production modelling; 2) Build-up of a large scale siRNA library for the dissection of ceramide production and signalling pathways; 3) LNAs being developed against our first Athero-Flux target.

WP1. Discovery of regulatory nodes within SL biosynthesis in coronary artery disease via flux lipidomics. We have been able to successfully differentiate iPSCs into hepatocytes that closely resemble liver cells by both functionality and by lipid composition. We are now able to efficiently label cell lines with stable isotopes targeted for sphingolipid metabolism, which will facilitate tracer experiments. Unique lipidomics platforms developed by Zora will enable us to absolutely quantify SL and ceramide species with distinct structural motifs.

WP2. Genome-scale RNAi screening to reveal rate-limiting pathways in ceramide metabolism and signalling. We made good progress in the generation of an siRNA screening library. Systems biology analysis of the data (WP1, WP2) is still ongoing to enrich the list of relevant targets to be further evaluated and validated in other WPs.

WP3. Study of the effect of prospective therapeutic targets within SL pathway on inflammatory signalling. In the previous reporting period we highlighted a crucial role for SL production in TNF signalling highlighting the important role of ceramide production in inflammatory signalling. In this reporting period, experiments have started to uncover the mechanisms responsible for this ceramide-induced inflammatory signalling.

WP4. Evaluation of biodistribution, bioactivity and pro-atherogenic properties of SLs. Major progress has been made towards the identification of the ceramide species that accumulate in the aortic wall of both wild-type and hyperlipidaemic mice with atherosclerosis. Work on the effect of disruptions in ceramide synthesis in metabolism and atherosclerosis has also progressed. Innovative in vitro assays have been developed to aid the characterisation of the effects of gut microflora on sphingolipid metabolism and atherosclerosis. Investigations into whether specific components of the microbiome affect the secretion of ceramide species are underway.

WP5 Development of LNA targeting SL metabolism and its associated signalling. In WP5, LNAs against a target involved in sphingolipid metabolism have been synthesised. Four LNAs that display powerful knockdown of the target in vitro and in vivo, two of which have safe pharmacology in mouse, have been generated and are ready for use by the beneficiaries of the consortium.

WP6. Management, Review and Assessment. There have been extensive management activities in the project. We have organised a Kick-off meeting in Oxford (UK) (October 2013) and annual meetings in Siena (Italy) (September 2014) and in Athens (November 2015). 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 phone call with members of the Steering Committee and Management Team to better harmonise and coordinate the Athero-Flux efforts.

WP7. Dissemination and Diffusion of project results. Dissemination of information about Athero-Flux is ongoing. A website has been established to provide public information on the project and dissemination activities have effectively brought the study to public attention at an international level. The conceptual challenge of the Athero-Flux project has been discussed in numerous international meetings and numerous articles acknowledging Athero-Flux funding have been published. A brochure summarising project objectives and outcome has been produced for distribution to the scientific community.

Potential Impact:
Athero-Flux will contribute to National and European Health by putting into practice new knowledge into hitherto untargeted lipids with strong prognostic predictive value in large scale clinical studies and ultimately generating new therapeutic tools with the latest oligonucleotide technology for gene silencing.
The most important impact of this proposal is the discovery of new therapeutic targets within SL metabolism that may abate the risk of previously unrecognized imbalances leading to the formation of structurally distinct SL. By defining in detail which sphingolipids and their synthetic enzymes are really important in pathogenesis of cardiovascular disease we will have new potential therapeutic targets and so will be in unique position to help validate these as targets and so define new therapeutics for a major disease. The selection and validation of targets will directly lead to a portfolio of 3rd generation antisense drugs that can enter a pipeline of clinical development and prelude to the generation of further therapeutics.

A second area of impact is the boost of the competitiveness of EU-based SMEs by strengthening the SME pipeline with opportunities to capitalize on unique research platforms (human samples, iPSCs and mouse models) and scientific discoveries in need of effective translation to the clinic. The planned workflow enables a two-way integration between the Academic and SME capabilities. The application of lipidomics by the SME to clinical trials has identified novel lipid mediators to target in CVD. The planned Academic and SME partnership will feed a significant number of potential targets into the SME pipeline.

The novelty of this proposal is the unique and multidisciplinary blend of academic and technical skills. Athero-Flux builds on established collaborations in previous EU Consortia but enriches their interaction by bringing in experts in SL metabolism, high-throughput RNAi screening, LNA platforms and gut microflora in a true multidisciplinary effort to achieve better treatment for CVD beyond hypolipidemic drugs. Technological advance also take center stage in Athero-Flux: novel lipidomics platforms will define the kinetic of the many existing SL and shed light on their production, while regulatory check-points will be validated with innovative LNA platforms and further defined with high-resolution cell phenotyping and signaling analysis with CyTOF. This injection of expertise and technological advances will fuel significant progress towards solving existing challenges in CVD, such as the deep relationship between lipid metabolism and signaling and inflammation that is fueling an increase of metabolic diseases in EU and worldwide.

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