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Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.3.2-3 | Award Amount: 17.07M | Year: 2010

This proposal is for a large scale collaborative project in which we propose both to develop novel microbicides directed against new intracellular targets and to investigate novel combinations of highly active anti-retroviral drugs which may be particularly effective as microbicides. Combinations may enhance efficacy but equally importantly will increase the genetic barrier to the development of resistance. The proposal includes development of both slow release and gel formulations, pharmacokinetic and challenge experiments in macaques as well as human studies including a collaborative study with an EDCTP-funded project to use multiplex and proteomic technologies as well as culture-independent DNA-based analysis of mucosal microbiota to investigate biomarkers and establish a baseline signature from which perturbations can be recognised. This is a large consortium comprising 30 partners from 8 EU countries and from Switzerland, Ukraine, South Africa and the United States.Partners include microbicide developers, IPM and Particle Sciences, and producers, Gilead, Tibotec and Virco. Two SMEs will also participate in RTD aspects. The consortium is multidisciplinary with scientists engaged in basic discovery working with new targets and developing novel chemistry to produce compounds with improved safety and efficacy profiles as well as altered patterns of resistance.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-1.4-1 | Award Amount: 15.92M | Year: 2010

Type 1 diabetes is a serious chronic disease with major health risks and heavy burden on patients and society. It is caused by massive immune-mediated loss of insulin-producing beta cells in the pancreas that can so far not be locally corrected. A cellular allotransplant in the liver can install a new beta cell mass but the size is insufficient and the procedure faces limitations of donor shortage, inaccessibility of the implants, risks of associated immunosuppression. Our consortium of research, clinical and bioindustry teams is focused on overcoming these obstacles and implementing a roadmap for translation to preclinical models and clinical trials. We will pursue three interacting tracks. First, our ability to induce beta cell progenitors and stimulate beta cell proliferation in vivo should lead us to cells and compounds that activate this process in a diabetic pancreas, thus activating endogenous beta cell regeneration. Second, we will produce human beta (progenitor) cells in vitro by derivation from stem cells as well as from reprogrammed autologous cells; their therapeutic potential will be compared to that of primary human beta cells following implantation in rodents using a site that is accessible to modulation and monitoring. Third, we will design an antibody-based therapy for inducing immune tolerance to regenerated beta cells and to a beta cell implant. Efficacy, safety and regulatory criteria will be determined for clinical implementation. Clinical protocols will be prepared by adjusting associated therapy and by adopting an accessible and controlled implant site. Clinical trials will benefit from state-of-the art biologic markers for comparative analysis of the developed forms of beta cell therapy. This program should provide proof of principle for strategies that make beta cell transplantation and beta cell regeneration realistic for large numbers of type 1 diabetic patients, and probably also for some categories of type 2 diabetes.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-6 | Award Amount: 4.23M | Year: 2011

Pancreatic cancer is one of the most lethal human cancers with a five-year survival rate of less than 5%. Late presentation and a high level of resistance to chemotherapeutic drugs are among the major reasons for this dismal prognosis. The presence of the highest degree of desmoplasia among all solid tumours and the fact that chronic inflammatory pancreatic disease is associated with an increased risk for pancreatic cancer indicate, that the tumour microenvironment is of particular importance for carcinogenesis in the pancreas. The long-term objective of this proposal is to increase survival of pancreatic cancer patients by exploring the contribution of the tumour microenvironment to the failure of presently available oncological treatments. For this purpose the clinical observation will be reverse-translated into innovative in-vitro and mouse models closely mimicking the human disease. This will allow a profound study of the mechanistic basis of treatment failure by deciphering the complex network between components of the microenvironment and cancer cells leading to increased resistance to chemotherapy and infiltrative growth along adjacent lymphatic and neural structures as well as metastatic spread. Identification of cancer (stem) cell-autonomous as well as stromal-derived mediators of invasion and chemoresistance will lead to novel drug targets to overcome the current therapeutic dilemma. The consortium has been specifically designed to include all required levels of expertise: 1) surgical and medical oncology groups conducting the largest clinical trials for pancreatic cancer in Europe, 2) expert pancreatic pathologists, 3) basic scientists focused on the study of carcinogenesis and tumour microenvironment interactions in the pancreas, 4) molecular oncology groups that have developed genetically engineered mouse models faithfully recapitulating human pancreatic cancer, as well as 5) pharmaceutical industry specialised on drug development.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-1.4-3 | Award Amount: 16.34M | Year: 2010

We propose to develop new strategies to mobilize skeletal muscle tissue-associated stem cells as a tool for efficient tissue repair. This will be combined with exploring novel approaches that limit tissue damage, and will focus on agents that modify muscle and muscle vasculature progenitor cells. These molecules include nitric oxide associated with non-steroidal anti-inflammatory drugs, HMGB1, Cripto, NAC, and present and improved deacetylase inhibitors. Three clinical trials will be run in tandem with efforts to dissect the underlying mechanisms of action. Importantly, we have already initiated a monocentric clinical trial that focuses on the efficacy of NO-donors plus NSAIDs in muscle pathologies. Our efforts will be complemented by novel biodelivery systems for effective targeting. Our efforts will be complemented by novel biodelivery systems for effective targeting. The most promising drugs, used alone or in combination, will be first validated in small and large animal models. Our project brings together leading investigators to examine how vascular and muscle progenitors participate in postnatal growth and muscle tissue repair. A key issue that this project addresses is the tissue environment in which endogenous stem cells are activated. We propose that muscle degeneration and fibrosis provokes altered vascularization and immune responses, which eventually affect negatively stem cell functions. Molecules that can be used to therapeutically target these key cells, and their communication with neighboring vascular, inflammatory and fibrotic cell types, will lead to more effective approaches to muscle regenerative medicine and to novel cures for degenerative diseases, including atherosclerosis, vascular damage in diabetes and in peripheral ischemic vascular disease.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.1.4-1 | Award Amount: 14.70M | Year: 2010

Preventing immunological rejection of transplanted organs without the need for long-term use of pharmacological immunosuppression is a primary objective in transplantation medicine. Reducing the need for immunosuppression would dramatically improve the outcome for transplant recipients and reduce health costs for society. The means to achieve this goal has not been realised with pharmacological or biological agents yet. Conditioning the immune response of solid organ transplant recipients towards allograft acceptance using cell-based therapies is now becoming technically feasible and clinically promising. The central focus of our proposed cooperative work programme is to produce distinct populations of haematopoietic regulatory cells and comparatively test their safety and efficacy in minimising pharmacological immunosuppression in solid organ transplantation. Preparations of regulatory T cells, macrophages and dendritic cells will be licensed for clinical manufacture in outstanding research facilities across Europe, and subsequently, these different tolerance-promoting cell types will be assessed in a single Phase I/II clinical study for safety, clinical practicality and efficacy. The therapeutic potential of these cells will be directly compared using one, single clinical protocol. In addition, we will study the tolerogenic characteristics of these regulatory cell types at in-depth molecular and functional levels. These integrative, but very focused, research plans are expected to result in the identification of the most promising regulatory cell products for further testing, and commercial exploitation: the final outcome is to identify a cell product which has genuine potential to induce operational tolerance if correctly applied in a Phase IIb clinical trial. This objective can only be accomplished by the cooperation of the most experienced researchers in this field across Europe, in alliance with SMEs devoted to cell therapy.


Grant
Agency: European Commission | Branch: FP7 | Program: CSA-CA | Phase: REGIONS | Award Amount: 2.79M | Year: 2010

The development of innovative Advanced Therapies offers new approaches to tackle major diseases such as cancer, diabetes, Alzheimer or Parkinson. The progress made in the fields of Tissue Engineering and Regenerative Medicine (TERM) promises to deliver long awaited new solutions. They are recognized as potential sources for medical progress and significant economic growth where Europe should position itself. Since advanced therapies are often based on personalized medicine, the translation of medical developments into real-life, sustainable therapies is challenged by several hurtles. We need new scientific (multi-disciplinary, GMP-conform research environment), economic (new business models for high-cost-low frequency treatments) and structural (translation-oriented RTD) solutions. Europe has to improve its research capacities and accelerate translation to catch up with the US and keep ahead of rapidly developing Asian countries. TERM project aims at a consolidating skills and infrastructures among European regions and their research clusters through the definition of joint actions and mentoring. The goal is to derive high potential, translation-oriented projects from joining skill-sets, infrastructures and networks and from recognizing the requirements of the market forces. The financing situation shall also be analyzed and adapted to the requirements. TERM project will develop knowledge and strategies on how to use resources of the regions and clusters more efficiently with more synergy and focus. The knowledge generated shall be used to develop tools to efficiently assess the research potential of a region, implement best practices in a research cluster, develop inter-regional programs with joined research goals and suggest financial instruments that support these efforts. Therefore, the output of our project will be the development of a European strategy, action plan and best practice tools on how to link research clusters from different regions


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.4-1 | Award Amount: 9.25M | Year: 2010

Leukodystrophies (LDs) are inherited rare neurodegenerative diseases of the white matter and its main component, the myelin, that are affecting predominantly children. Severity of the disease is related to the axonal dysfunction due to myelin deficiency or destruction. Despite the achievement of remarkable advances made in the past decade, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection constitutes the main objective of the LeukoTreat project. Indeed LDs constitute prototypic pathologies to tackle myelin formation/destruction issues as well as glial cells dysfunctions in neurodegeneration. The global aim is to promote the development of therapeutic strategies for the largest number of LD affected patients and further applications to more common white matter disorders and finally neurodegenerative diseases. For this purpose, the project will combine the expertise of (i) recognized European research teams in the field of White Matter diseases (COST Myelinet), (ii) high-technology SMEs, (iii) experts in medical ethics and (iv) LD patients and families associations. To develop efficient therapies, the LeukoTreat project is based on 5 complementary approaches consisting in: (i) collecting information on the epidemiology, the natural history, the genotype/phenotype correlation of LDs for at least 500 patients; (ii) validating/identifying biomarkers for therapeutic decisions/follow up to isolate new therapeutic targets; (iii) developing pharmacological strategies with the ultimate objective to launch at least 4 pharmacological clinical trials during 5 years following the project; (iv) developing innovative gene and cell therapies with the ultimate objective to launch at least 3 clinical trials during the next 5 years; (v) tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics


Hematopoietic stem cell gene therapy has a tremendous potential to treat human disease. Yet, in conjunction with the first successful results in the clinic, severe adverse events linked to the gene transfer protocol were reported. Recently, we provided proof-of-principle of two new powerful strategies to improve the efficacy and safety of gene transfer: 1) regulating transgene expression by exploiting cellular microRNAs; 2) targeting integration at predetermined sites of the genome by forcing homologous recombination with designer Zinc finger nucleases. Here we will investigate the microRNA network regulating hematopoiesis and exploit the new knowledge to develop vectors with stringently controlled expression throughout the hematopoietic lineages. We will develop Zinc finger nuclease-based vectors that insert the transgene with high efficiency and specificity either downstream to its own endogenous promoter or into a safe genomic harbor that allows for robust expression without interference on the neighboring genes. By combining these strategies we will provide radically improved gene transfer platforms. Furthermore, we will exploit these technologies for the generation and genetic correction of induced pluripotent stem cells, providing a potentially unlimited source of patient-derived vector free gene corrected multipotent stem cells for future applications of regenerative medicine. The new gene therapy strategies will be tested in pre-clinical models of leukodystrophies and immunodeficiencies, for which we have extensive experience, and should enter a clinical trial for at least one such disease by the end of the proposed funding period. If successfully validated, the new strategies may eventually broaden the scope of gene therapy in medicine.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IIF | Phase: FP7-PEOPLE-2010-IIF | Award Amount: 181.08K | Year: 2012

Transcription factors (TFs) are capable to identify their target sites on DNA in a extremely efficient fashion. The observation that a simple 3D diffusion search cannot account for such efficient targeting has led to different mechanisms to be proposed in the last decades, including compact exploration induced by facilitated diffusion (i.e. combination of 1D sliding and 3D diffusion) or by fractal-like chromatin structure. Despite the evidence for 1D sliding of TFs on DNA and for fractal nuclear organization, it still needs to be demonstrated that these phenomena play a significant role in the TF search mechanism in a living cell. Fluorescence microscopy and in particular single molecule tracking (SMT) provides an excellent tool to investigate the kinetics of proteins in living samples. SMT has mostly been applied to in-vitro and in-membrane environments due to limitations associated to prolonged 3D tracking. In this project we plan to overcome the limitations associated to 3D SMT and to apply the developed technology to investigate the in-vivo search mechanisms of p53, an important TF, involved in the determination of the cell fate under stress conditions. We aim to quantify the role of compact exploration in p53 targeting in living cells, and by the analysis of mutated p53 how 1D sliding affects such phenomenon. Furthermore, we plan to identify the changes in the p53-DNA association and in the p53 search after induction of cell stress by DNA damage. Summarizing, the project aims to strongly improve current methods for tracking individual molecules in 3D and to advance our knowledge about the mechanisms of TF targeting.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 3.25M | Year: 2011

The recent identification of tumor initiating (TIC) or cancer stem cells (CSC) has opened a new area of research for scientists interested in cancer. Understanding the biology of cancer stem cells has already unraveled pathways and potential targets. However, accumulating data has underscored the complexity of the CSC research area and prompts hence the need for well-structured networks to provide expert platforms, rapid exchange of information to train future researchers in this new concept. 10 laboratories from 6 member states with 4 expert enterprises, all at the highest level of cancer stem cell research will unit in a European Cancer Stem Cell Training Network (EuroCSCTraining). Partners, from the public and private sector, have complementary expert experience in this new area, are active members of CSC research, and share dedication in training and dissemination. The EuroCSCTraining coordinator is one of the present coordinators of the Paris CSC Consortium and director of the Institute of PhD schools of University Paris-Diderot. The main goal of this Network is to foster translaboratory and transPhD school training in this new area of Cancer Research. The EurosCSCTraining supervisory board will bring together supervisors of the private and public sector along with representatives of PhD schools to provide eligibility criteria of recruitment, monitor training, and set up individual tutorship for PCD. The research projects on cancer stem cells will be advertised simultaneously through the EuroCSCTraining Network and the partners University. It is anticipated that the EuroCSCTraining network will create a multidisciplinary and multisector structure of training for a new area of research in cancer which will develop research in Europe, foster European collaborations and provide the basis to harmonise initial research training in cancer research amongst partner Institutions.

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