Embryonic Stem cell-based Novel Alternative Testing Strategies

1. The ESNATS Project –Health call 2007 A Embryonic Stem cell-based Novel Alternative Testing Strategies The aim of the ESNATS project is to develop a novel "all-in-one" toxicity test platform based onembryonic stem cells, in particular human ESC (hESCs), to accelerate drug development, reduce related R&D costs and propose a powerful alternative to animal tests 15,839,072 €Cost: Req.: 11,895,577 € Israeli partners CELL CURE offers to use hESC as a platform for CNS toxicity screening (both developmental and acute/subacute) based on existing tools and established capabilities for generation of multipotent neural precursors and midbrain dopaminergic neurons and for their characterisation 176,400 € Other major partners

2. The ESNATS Project –Health call 2007 A ESNATS aims at developing a novel toxicity test platform based on embryonic stem cells (ESC), especially human ESC (hESC), to accelerate drug development, reduce R&D costs and propose a powerful alternative to animal tests (3 Rs). ESNATS will address current drug-testing shortcomings: - testing takes place late in the development cycle - animal test systems bear the risk of non-prediction due to inter-species variation - non-ESC assays rely on primary cells or cells of malignant origin that are hard-to-standardise and limited in regard to quantity, homogeneity and genetic diversity • existing assay systems based on primary animal cell lines do not reliably represent the physiological situation ESNATS will develop a battery of toxicity tests using hESC lines subjected to different standardised culture protocols. Tests will cover embryoid bodies in different developmental stages and differentiated derivatives including gamete and neuronal lineages, complemented with test systems for hepatic metabolism. Predictive toxicogenomics and proteomics markers will be identified. The individual tests will be integrated into an "all-in-one" test system. To enable future industrial use ESNATS will prepare automating and scaling up of hESC culture. The predictivity, quality and reproducibility of ESNATS will be evaluated in a proof of concept study. ESNATS benefits are to increase safety due to better predictivity of human test systems, to reduce, refine and replace animal tests, to lower testing cost, and to support medium/high throughput testing. ESNATS objectives will be achieved in a 5 year multi-disciplinary collaboration of leading European researchers in alternative testing, toxicology, ESC research, genomics, modelling, and automation. The consortium will also include representatives from regulatory bodies, the pharmaceutical industry and ethical advisors to provide guidance to ensure rapid applicability of the developed tests systems.

3. The PLASTICISE Project – Health call 2007 B New ways of promoting plasticity in the adult brain following a damage The focus of the PLASTICISE project is the development of new treatments to promote plasticity and of methods to measure and visualize their effects, focusing on Alzheimer’s disease, stroke and damaged visual system. €7,783,602Cost: Req.: 5,999,445 € Israeli partners D-Pharm’s MAC technology uses lipids to develop small molecule drugs that can specifically function only within the lipid environment of cell membranes 173,392 € Other major partners

4. The PLASTICISE Project – Health call 2007 B Neurodegenerative diseases all cause damage to the circuitry of the nervous system, with loss of connections, axons and neurons. The loss can be gradual, as in Alzheimer’s disease, rapid as in stroke, or intermediate as in the delayed neuronal loss after stroke. Following damage, the nervous system is able partially to compensate through the formation of alternative connections and pathways, a process known as plasticity. Adults are therefore able to regain considerable function after stroke, and to compensate for the synapse and cell loss of Alzheimer’s disease until it reaches a critical level. Children undergo a period of enhanced plasticity in most parts of the CNS at the end of development, known as critical periods. During these periods their ability to compensate for damage to the CNS is in many cases much greater than in adults. The overall concept behind this application is that restoration of the function in neurodegeneration can be achieved through plasticity (the formation of new functional connections, withdrawal of inappropriate connections, modulation of synaptic strength). Promoting increased plasticity in selected parts of the adult nervous system back to the level seen in children is a powerful method of enhancing recovery of function in animal models. Plasticity-promoting treatments could therefore be beneficial in a wide range of conditions that damage the CNS. The PLASTICISE project integrates scientists from four scientific areas 1) Development of methods to promote plasticity 2) Development of models of neurodegenerative disease 3) Imaging of plasticity at the macro and micro level 4) Study of recovery of function through plasticity in human patients with brain disorders. The concept that unites the partners is the belief that treatments that enhance plasticity will become one of key medications that will improve neurological function in the damaged human nervous system. The purpose of the project is to bring this moment closer.

5. The EUROTRAPS Project – Health call 2007 A Natural course, pathophysiology, models for early diagnosis, prevention and innovative treatment of TNF Receptor Associated Periodic Syndrome (TRAPS) with application for all hereditary recurrent 3,840,773 €Cost: Req.: 2,963,227 € Israeli partners Pronto Diagnostics Ltd. 322,150 € Other major partners

6. The EUROTRAPS Project – Health call 2007 A The TNF Receptor Associated Syndrome (TRAPS) is a rare disease of innate immunity, caused by mutations in TNFR1. It is characterized by recurrent bouts of fever and pain and mainly affects patients of European ancestry. The development of renal amyloidosis in up to 20% of cases makes it a potentially fatal disease. Corticosteroids and anti-TNF therapeutics have not been consistently effective in controlling attacks and preventing amyloidosis. EUROTRAPS is a multidisciplinary consortium, which by combining ideas, resources, and data from 7 academic participants and 2 SMEs from 6 countries, aims to gain insights into the natural course and pathophysiology of TRAPS, particularly in children. The creation of a European registry for TRAPS patients will facilitate the delineation of scores and outcome measures for diagnosis and treatment. We will examine additional pathways and genes involved in the phenotype. Kit assays will be developed to facilitate identification of disease mutations and susceptibility factors for amyloidosis and resistance to treatment. TNFR1 signalling, apoptosis and IL1 secretion abnormalities associated with TRAPS will be studied. We will also develop in vitro and humanised animal models to investigate innovative therapies. We expect that future developments in TRAPS will impact on all aspects of hereditary paediatric fevers, and thereby improve the wellbeing of patients and their families. A dedicated bipartite committee will undertake the complex task of managing this ambitious project, create a secure intranet, organize regular meetings, issue progress reports, oversee ethical, legal, financial, and gender issues (over 50% of the participants are female), adjust the workplan at each milestone, and guarantee dissemination, exploitation and protection of scientific information. The requested funding will cover salaries (over 200 person/months newly generated employments), equipment acquisition, consumables, and dissemination of knowledge.

7. The CAREPNEUMO Project – Health call 2007 B Combating Antibiotics Resistant Pneumococci by Novel Strategies Based on in vivo and in vitro Host – Pathogen Interactions Aim 1: epidemiology of drug resistance and vaccine pressure replacement of S. pneumoniae Aim 2: analysis of host-pathogen interactions and identification of potential therapeutic targets and vaccine candidates Aim 3: development of improved vaccine and intervention strategies 3,969,999 €Cost: Req.: 2,999,999 € Israeli partners Protea Vaccine Technologies Ltd. 171,450 € Other major partners

8. The CAREPNEUMO Project – Health call 2007 B The diseases caused by Streptococcus pneumoniae are a major public health problem all over the world. Children, elderly people and immunocompromised individuals are the high-risk targets for pneumococcal diseases. In spite of the availability of a large number of antibiotics the mortality and morbidity due to S. pneumoniae infections remain very high. There are two reasons for this: Firstly, the increasing antibiotic resistance among pneumococcal strains, and secondly, a current vaccine, though effective for certain serotypes, leads to serotype replacement. For the development of combat strategies it is essential to identify new intervention strategies, for which an understanding of host-pathogeninteraction is a prerequisite. This proposal would apply a multi-disciplinary approach that includes epidemiology, host-pathogen interactions, infection models and intervention strategies to combat antibiotic resistant S. pneumoniae. The consortium brings together 12 research organizations and 1 SME with expertise in the above-mentioned areas. The major objectives of this consortium will be 1. monitoring of prevalent S. pneumoniae serotypes and their resistance profiles in different countries, 2. analysis of host-pathogen interactions and identification of potential therapeutic targets and vaccine candidates, 3. providing a basis for the development of improved vaccine and intervention strategies. This joint international effort would contribute towards novel control strategies, especially of antibiotic resistant S. pneumoniae strains.

9. The HYPERGENES Project – Health call 2007 A European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model The aim of our integrated approach is to develop an exhaustive model to disentangle the genetic bases of a complex disease using population genetic epidemiology as a methodological tool. 14,839,460 €Cost: Req.: 10,547,420 € Israeli partners IBM Israel - Science and Technology LTD 1,595,500 € IBM-HRL is involved with two groups: the IT Healthcare and Life Science research group in HRL, lead by Dr Haim Nelken, focuses on IT services and solutions for the HC &LS markets. the Machine Learning research group in HRL, lead by Dr. Shai Fine, focuses on providing data driven solutions in various domains that include both general purpose and problem specific tools and content. Other major partners http://www.smesgohealth.org/media/documents/SOFTECO_success_story.pdf

10. The HYPERGENES Project – Health call 2007 A The project is focused on the definition of a comprehensive genetic epidemiological model of complex traits like Essential Hypertension (EH) and intermediate phenotypes of hypertension dependent/associated Target Organ Damages (TOD). To identify the common genetic variants relevant for the pathogenesis of EH and TODs, we will perform a Whole Genome Association (WGA) study of 4.000 subjects recruited from historical well-characterized European cohorts. Genotyping will be done with the Illumina Human 1M BeadChip. Well-established multi-variate techniques and innovative genomic analyses through machine learning techniques will be used for the WGA investigations. Using machine learning approach we aim at developing a disease model of EH integrating the available information on EH and TOD with relevant validated pathways and genetic/environmental information to mimic the clinician's recognition pattern of EH/TOD and their causes in an individual patient. Our statistical design is with two samples run in parallel, each with 1,000 cases and 1,000 controls, followed by a replication/joint analysis. This design is more powerful than replication alone and allows also a formal testing of the potential heterogeneity of findings compared to a single step (one large sample) design. The results represent the source to build a customized and inexpensive genetic diagnostic chip that can be validated in our existing cohorts (n=12,000 subjects). HYPERGENES is in the unique position to propose a ground-breaking project, improving the methodology of genetic epidemiology of chronic complex diseases that have a high prevalence among EU populations. Designing a comprehensive genetic epidemiological model of complex traits will also help us to translate genetic findings into improved diagnostic accuracy and new strategies for early detection, prevention and eventually personalised treatment of a complex trait. The ultimate goal will be to promote the quality of life of EU populations.

11. The MASTERSWITCH Project – Health call 2007 B Mechanisms to Attack Steering Effectors of Rheumatoid Syndromes with Innovated Therapy Choices To delineate the biological and molecular pathways that initiate and drive chronic inflammatory disease and to transform the knowledge obtained into the development of novel anti-inflammatory interventions. 15,249,039 €Cost: Req.: 11,888,749 € Israeli partners MaimoniDex RA Ltd 412,500 € Other major partners

12. The MASTERSWITCH Project – Health call 2007 B Objective: To delineate the biological and molecular pathways that initiate and drive chronic inflammatory disease and to transform the knowledge obtained into the development of novel anti-inflammatory interventions. Focus will be given to Rheumatoid Arthritis (RA) since longitudinal data indicate that intensive treatment can prevent persistency and chronicity. State of the Art and beyond: The first generation of targeted therapies in chronic inflammatory disease used RA as prototype disease for clinical development. These therapies are now also used in other inflammatory disorders. Although treatments have been developed that are effective in a proportion of patients, they are a specific, relatively toxic and do not mediate cure. Currently, it is unknown which molecular effects need to be induced and/or targeted to prevent induction or persistency of RA. However, this is within reach through a strong international consortium of world-leading European groups that cover both basic- and translational research. Work plan: The general strategy for the project is to enable parallel studies that are focused on critical switch moments in the biological processes that drive chronicity of inflammation. As the consortium consists of a multidisciplinary team with basic- and clinical expertise, translational research will be conducted to delineate the molecular basis of deregulated inflammation, the RA-specific autoimmune-response and organ specific pathobiology. The final aim is to develop novel- and specific anti-inflammatory therapies. Impact of the project: This project will (i) identify the molecular networks underlying chronic inflammation and thereby (ii) will define novel targets for drug-development as well as (iii) algorithms that will predict outcome of therapy. Moreover, within this project European SMEs will evaluate new interventions (iv) and this project will (v) offer a platform to rapidly develop ideas and patents into new therapies.