Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-15-2015 | Award Amount: 6.83M | Year: 2016
CLINICAL PROBLEM AND UNMET NEED There are 11,827 patients with severe structural airway disease in Europe. Even with the current standard of care, when hospitalised this group of patients has a 22% risk of dying. Patients are currently subjected to repeated surgical interventions (stent insertion) which have a high failure rate. Other therapeutic strategies under development include synthetic tracheal scaffolds seeded with patients own stem cells. Preliminary data show that these scaffolds are poorly integrated and are susceptible to infection. TETRA PROJECT Our SME-led project will address the limitations of standard clinical care and competitor products under development and will: - Build on our successful compassionate use experience using autologous stem cell seeded scaffold-tracheal transplants in 48 patients - Follow on from our Phase I 4 patient INSPIRE clinical trial which will improve on the clinical prototype used in compassionate use cases - Conduct a 48 patient Phase II pivotal clinical trial to provide robust, quality data with validated GMP manufacturing processes to support an accelerated route to market for commercial exploitation in this orphan indication - Prepare a dossier for MAA submission BENEFITS Our product, an ATMP, aims to eliminate the need for repeated surgical interventions of high risk and limited efficacy, reduce deaths and improve the quality of life for surviving patients. If treating 20% of the patients with severe structural airway disease, we estimate that in Europe our technology will improve the quality and length of patient lives and result in savings of 517 million per year. We plan to further develop our platform technology to generate other complex tissues/organs such as bowel and liver replacements for clinical applications which will impact the lives of tens of thousands of patient in the EU with bowel and liver diseases.
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.2.1-1 | Award Amount: 39.56M | Year: 2013
Traumatic Brain Injury (TBI) is a major cause of death and disability, leading to great personal suffering to victim and relatives, as well as huge direct and indirect costs to society. Strong ethical, medical, social and health economic reasons therefore exist for improving treatment. The CENTER-TBI project will collect a prospective, contemporary, highly granular, observational dataset of 5400 patients, which will be used for better characterization of TBI and for Comparative Effectiveness Research (CER). The generalisability of our results will be reinforced by a contemporaneous registry level data collection in 15-25,000 patients. Our conceptual approach is to exploit the heterogeneity in biology, care, and outcome of TBI, to discover novel pathophysiology, refine disease characterization, and identify effective clinical interventions. Key elements are the use of emerging technologies (biomarkers, genomics and advanced MR imaging) in large numbers of patients, across the entire course of TBI (from injury to late outcome) and across all severities of injury (mild to severe). Improved characterization with these tools will aid Precision Medicine, a concept recently advocated by the US National Academy of Science, facilitating targeted management for individual patients. Our consortium includes leading experts and will bring outstanding biostatistical and neuroinformatics expertise to the project. Collaborations with external partners, other FP7 consortia, and international links within InTBIR, will greatly augment scientific resources and broaden the global scope of our research. We anticipate that the project could revolutionize our view of TBI, leading to more effective and efficient therapy, thus improving outcome and reducing costs. These outcomes reflect the goals of CER to assist consumers, clinicians, health care purchasers, and policy makers to make informed decisions, and will improve healthcare at both individual and population levels.
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-13-2014 | Award Amount: 5.99M | Year: 2015
Type 2 diabetes will affect >500 million adults by 2040 and its secondary complications will generate enormous socioeconomic costs - in particular, diabetic kidney disease (DKD), which is already the most common cause of chronic kidney disease. DKD is associated with greatly increased mortality and frequently progresses to end stage renal failure. Pharmacotherapy, dialysis and transplantation represent the mainstay treatments for DKD but are costly and provide only limited protection against adverse outcomes. Mesenchymal Stromal Cell (MSC) therapy is a promising approach to halting the progression of DKD toward end-stage renal failure and may also have ancillary benefits in Type 2 diabetes. In preliminary research, we have demonstrated that a single dose of MSC simultaneously improves kidney function (glomerular filtration rate and albuminuria) as well as hyperglycaemia in animals with DKD. NEPHSTROM will conduct a multi-centre, placebo-controlled clinical trial of a novel MSC therapy for stabilization of progressive DKD, leading to superior clinical outcomes and long-term socioeconomic benefit. A key enabler for this trial is a novel MSC population (CD362\MSC, trade name ORBCEL-M) which delivers higher purity and improved characterisation compared to conventional plastic-adherent MSC. The NEPHSTROM Phase 1b/2a clinical trial will investigate the safety, tolerability and preliminary efficacy of a single intravenous infusion of allogeneic ORBCEL-M versus placebo in adults with progressive DKD. NEPHSTROM investigators will also determine the bio-distribution, mechanisms of action, immunological effects and economic impacts associated with ORBCEL-M therapy for DKD. This research will critically inform the optimal design of subsequent Phase 3 trials of ORBCEL-M. Stabilising progressive DKD through NEPHSTROMs next-generation MSC therapy will reduce the high all-cause mortality and end-stage renal failure risk in people with this chronic non-communicable disease
News Article | November 17, 2016
A team of Cambridge researchers led by scientists at the Babraham Institute have discovered the hidden connections in our genomes that contribute to common diseases. Using a pioneering technique developed at the Babraham Institute, the results are beginning to make biological sense of the mountains of genetic data linking very small changes in our DNA sequence to our risk of disease. Discovering these missing links will inform the design of new drugs and future treatments for a range of diseases, including rheumatoid arthritis and other types of autoimmune disease. Comparing the genome sequences of hundreds of thousands of patients and healthy volunteers has revealed single-letter changes found more frequently in the DNA sequences of individuals with specific diseases. In most cases, the disease-linked changes occur in the large swaths of DNA located between genes, often referred to as junk DNA. The fact that the changes are not in or near genes has made it challenging to understand how they could cause disease. Now, as reported in the leading journal Cell, the Promoter Capture Hi-C technique is being used to fill in the missing pieces by charting interactions between genes and sequences far away on the DNA thread. The Promoter Capture Hi-C technique works by identifying parts of the genome that physically contact and regulate genes. The long thread of DNA is highly folded inside cells, allowing regions very far apart on the thread to contact each other directly. Dr Peter Fraser, Head of the BBSRC-funded Nuclear Dynamics research programme at the Babraham Institute which coordinated the study and a senior author on the paper, explained: "By identifying which parts of the genome connect with which genes we have discovered hundreds of thousands of regions that are necessary to switch genes on and off. Small changes to the DNA sequence of these distal regulatory regions can interfere with the normal control of genes, leading to a greater chance of developing a specific disease. The power of this approach is that it allows us to make biological sense of very tiny changes in the genome that have big impacts on health." By mapping the regions of the genome that interact with genes in 17 different blood cell types the researchers were able to create an "atlas" of contacts between genes and the remote regions that regulate them in each cell type. They then matched this information to known changes in DNA at these regions that are linked to specific diseases. This allowed them to uncover which genes are affected by these DNA changes, pointing to their roles in disease. The different blood cell types were obtained from blood samples donated by healthy volunteers of the NIHR Cambridge BioResource or by culture of blood stem cells in the laboratory of Dr Mattia Frontini, leader of the blood cell epigenome team at the University of Cambridge's Department of Haematology. Professor John Todd, Director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory and founder and former principal investigator of the Cambridge BioResource said: "These results are a giant leap in understanding the inherited and cellular origins of common diseases and in how the human genome works." The team found thousands of new genes linked to specific diseases, including autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and Crohn's disease that are currently incurable and notoriously difficult to treat or prevent. This knowledge could enable new drugs to be designed targeting those genes, or repurposing of already existing drugs to treat these conditions. Dr Mikhail Spivakov, group leader in the Nuclear Dynamics research programme at the Babraham Institute and a senior author on the paper, said: "Mapping the genome's regulatory interactions establishes the missing link between a genetic change at one part of the genome with the gene it ultimately affects. While the results currently look promising, it will take many more years of work and rigorous testing before new treatments become available as a result of this fundamental research". As a large multi-partner study, this research was collaboratively undertaken by the Babraham Institute, the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory in the Cambridge Institute for Medical Research and the Departments of Medicine and Haematology at the University of Cambridge, the EMBL-European Bioinformatics Institute, the NHS Blood and Transplant organisation and the MRC Biostatistics Unit. The research was funded by a grant from the Medical Research Council whereas the researchers and organisations involved are supported by several funders including the UK's Biotechnology and Biological Sciences Research Council, the British Heart Foundation, the Juvenile Diabetes Research Foundation (JDRF) and the Wellcome Trust in addition to funding from the European Commission (multiple sources).
News Article | November 17, 2016
As part of the BLUEPRINT project, scientists have discovered how variation in blood cell characteristics and numbers affects the risk of complex diseases such as heart disease and autoimmune diseases including rheumatoid arthritis and type 1 diabetes Today in Cell and associated journals, 24 research studies from the landmark BLUEPRINT project and IHEC consortia reveal how variation in blood cells' characteristics and numbers can affect a person's risk of developing complex diseases such as heart disease, and autoimmune diseases including rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes. The papers, along with another 17 in other high-impact journals, are the culmination of a five-year, £25 million (€30 million) project that brought together 42 leading European universities, research institutes and industry partners. The project's goals were to explore and describe the range of epigenetic changes that take place in bone marrow as stem cells develop into different types of mature blood cell. It also sought to match epigenetic changes and genetic differences to the physical characteristics of each cell type and use this knowledge to understand how these can lead to blood disorders, cancer and other complex diseases*. As part of BLUEPRINT, Wellcome Trust Sanger Institute led two of the six papers being published in the journal Cell today. In the first study, Sanger Institute researchers worked closely with colleagues at the University of Cambridge and the University of Oxford to carry out the largest and most in-depth study of DNA and blood cell characteristics using the UK BioBank resource and the INTERVAL study**. By comparing almost 30 million DNA sequence differences in more than 173,000 people with variation in the physical properties of blood cells the scientists identified 2,500 previously undiscovered locations in the genome that influence blood cell characteristics and functions. Further work showed that genetic differences affecting some of these characteristics are linked to increased risk of heart attack, or to rheumatoid arthritis and other common autoimmune diseases. Dr William Astle, from the University of Cambridge said: "The scale, resolution and homogeneity of our work were vital. Because we examined so many people we were able to discover important 'rare and low frequency' genetic differences that are present in fewer than 10 per cent of the population. We found that these can have a much larger impact on the characteristics of blood cells than the common differences studied previously. Of the more than 300 rare and low frequency difference we found, 74 appear to affect the structure of proteins. These give us important clues as to which biological pathways are involved in controlling the production, function and characteristics of blood cells." The team found that genetic differences that cause people to have more young red blood cells in their peripheral bloodstreams also increase the risk they will have a heart attack. Dr Adam Butterworth, one of the study's senior authors, from the University of Cambridge said: "When mature red blood cells rupture in our blood the body replaces them with new, young red cells - a process known as haemolysis. So we think that increased haemolysis and increased risk of coronary heart disease are affected by the same biological pathways. Identifying these pathways may offer new treatment possibilities." In another new finding, the research team showed that genetic differences that increased the amount of certain white blood cells, known as eosinophils, also increased the risk of a person developing rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes. In the second Cell paper, researchers collaborated with scientists at the University of Cambridge, McGill University in Canada and several UK and European institutions to explore the role that epigenetics plays in the development and function of three major human immune cell types: CD14+ monocytes, CD16+ neutrophils and naïve CD4+ T cells, from the genomes of 197 individuals. They studied the contributions of various genetic control mechanisms, including epigenetic changes such as methyl tags on promoter regions in the DNA and histone modifications, to understand how these different levels of regulation interacted with genetic differences to change the expression of genes, immune function and, ultimately, human disease. The team identified 345 regions of the genome where they could pinpoint the likely molecular causes underlying a person's predisposition to immune-related diseases such as inflammatory bowel disease, type 1 diabetes and multiple sclerosis. Dr Tomi Pastinen, senior author on the second study, from McGill University said: "We have created an expansive, high-resolution atlas of variations that deepens our understanding of the interplay between the genetic and epigenetic machinery that drives the three primary cells of the human immune system. We have identified hundreds of genetic variations associated with autoimmune diseases that appear to affect the activity of genes in specific regions of the genome, pointing to biological pathways that may be involved in disease and which, ultimately, may be treatable with medication." Professor Nicole Soranzo, senior author on both studies from the Sanger Institute and University of Cambridge, added: "The BLUEPRINT project has provided the worldwide research community with detailed insights and understandings that will form the basis of important blood cell research for many years to come. When integrated with large-scale genetic studies, these results and data inform understanding of how differences in the human genome and epigenome interact to cause devastating common diseases, and inform new avenues for treating these conditions." 1. Astle WJ et al. (2016) The allelic landscape of human blood cell trait variation and links to common complex disease. Cell http://dx. 2. Chen L et al. (2016) Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell http://dx. One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome - the epigenome - which acts as a blueprint unique to each cell type and developmental stage. Unlike the genome the epigenome changes as cells develop and in response to changes in the environment. Defects in the factors that read, write and erase the epigenetic blueprint are involved in many diseases. The comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes. A collection of 42 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. A set of 24 manuscripts has been released as a package in Cell and Cell Press-associated journals, and an additional 17 papers have been published in other high-impact journals. These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, South Korea, and the United States. The collection of publications showcases the achievements and scientific progress made by IHEC in core areas of current epigenetic investigations. For a full list of all 42 participating centres participating in BLUEPRINT, please see: http://www. BLUEPRINT is a large-scale research project receiving close to 30 million euro funding from the EU and involving 41 leading European universities, research institutes and industry entrepreneurs. The BLUEPRINT project aims to further the understanding of how our genes are activated or repressed in both healthy and diseased human cells. It aims to generate at least 100 reference epigenomes and study them to advance and exploit knowledge of the underlying biological processes and mechanisms in health and disease. http://www. The International Human Epigenome Consortium (IHEC) is a global consortium with the primary goal of providing free access to high-resolution reference human epigenome maps for normal and disease cell types to the research community. The epigenome reference maps will be of great utility in basic and applied research. They are likely to have an immediate impact on the understanding of many diseases, and will hopefully lead to the discovery of new means to treat or manage them. In addition to this work, many members support related projects to improve epigenomic technologies, investigate epigenetic regulation in disease processes, and explore broader gene-environment interactions in human health. IHEC will facilitate communication among the members and offer a forum for coordination, with the objective of avoiding redundant research efforts, implementing high data quality standards, and thus maximizing efficiency among the scientists working to understand, treat, and prevent diseases. http://ihec-epigenomes. Coronary heart disease is the UK's single biggest killer. For over 50 years we've pioneered research that's transformed the lives of people living with heart and circulatory conditions. Our work has been central to the discoveries of vital treatments that are changing the fight against heart disease. But so many people still need our help. From babies born with life-threatening heart problems to the many Mums, Dads and Grandparents who survive a heart attack and endure the daily battles of heart failure. Join our fight for every heartbeat in the UK. Every pound raised, minute of your time and donation to our shops will help make a difference to people's lives. For more information visit https:/ With some 300 buildings, 40,000 students, 250,000 living alumni, and a reputation for excellence that reaches around the globe, McGill has carved out a spot among the world's greatest universities. https:/ NHS Blood and Transplant (NHSBT) is a joint England and Wales Special Health Authority. Its remit includes the provision of a reliable, efficient supply of blood, platelets, plasma and associated services to the NHS in England. It is also the organ donor organisation for the UK and is responsible for matching and allocating donated organs. http://www. UK Biobank is a major national and international health resource, and a registered charity in its own right, with the aim of improving the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses - including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression and forms of dementia. UK Biobank recruited 500,000 people aged between 40-69 years in 2006-2010 from across the country to take part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed information about themselves and agreed to have their health followed. Over many years this will build into a powerful resource to help scientists discover why some people develop particular diseases and others do not. https:/ The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 90 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 12 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation. http://www. The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www. Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. http://www.
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.1.4-1 | Award Amount: 7.03M | Year: 2014
Prevalence of liver disease is c6% (29 million people) in the EU with mortality rates from chronic liver diseases estimated at 14.3 per 100.000 in the EU-25 in 2004. Most liver diseases have a significant inflammatory component that underpins liver damage and fibrogenesis, yet current therapies have limited effectiveness. Safe novel anti-inflammatory therapies would satisfy a large unmet need for inflammatory liver conditions such as primary sclerosing cholangitis (PSC). Mesenchymal Stromal Cells (MSC) are a mixed population of plastic-adherent (PA) cells isolated from bone marrow, umbilical cord and adipose tissue. Preclinical studies show that intravenous administration of PA-MSC reduces liver inflammation/damage, however only one MSC-based clinical study has been reported to date. MERLIN will examine if MSC can safely reduce biliary damage in mouse models followed by a clinical study in patients with PSC. We have identified an antibody (S2) that isolates comparable MSC from human & mouse marrow, enabling testing of pure functionally distinct cell S2\ & S2- and PA-MSC populations. We will use the worlds first GMP-compliant non-bead-based cell sorter to select S2\ MSC to comply with future therapeutic regulatory requirements. MERLIN partners will use novel methods to enhance MSC efficacy in PSC - by reducing immune clearance of MSC & by promoting MSC functionality & localisation in vivo. We will assess if MSC sub-sets exert differing levels of control upon liver inflammation in pre-clinical models, as well as defining their proliferation and mechanism of action. We will develop entirely novel biomarkers for PSC within the disease pathway pre and post cell infusion. The optimal combination of MSC sub-set and efficacy enhancement, will be selected for progression to a Phase 2 clinical safety study in patients with PSC. MERLIN will deliver a comprehensive data-set on optimised purified MSC and their efficacy/safety in pre-clinical models prior to a clinical trial in patients with PSC.
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.4-1 | Award Amount: 3.74M | Year: 2012
The presence of donor specific HLA antibodies is a contra-indication for renal transplantation. Highly sensitized patients accumulate and often die on the transplant waiting lists as it is almost impossible to find donors towards which they dont have antibodies. The acceptable mismatch program of Eurotransplant has shown to be an effective tool to enhance successful transplantation of highly sensitized patients. However, 35% of the patients have rare HLA phenotypes and no suitable donor can be found. HLA phenotype frequencies vary amongst European populations. Rare HLA phenotypes in one population are more frequent in other populations. The major objective of the 10 partners in this project is to analyze the feasibility and requirements for a Europe-wide acceptable mismatch program to enhance transplantation of patients with rare HLA phenotypes in their own population. Long waiting patients will be matched with virtual donors based on known HLA frequencies of different European populations and with actual donors from the different transplant organizations. If successful, the logistics will be tested by transplanting some of these patients with donors from elsewhere in Europe. Second objective is to simplify the definition of acceptable HLA mismatches. Although almost 4000 HLA class I antigens are known, only 150 polymorphic residues differentially spread over the different HLA antigens are responsible for the induction of antibodies. An innovative typing and matching strategy based on the definition of acceptable HLA epitopes will facilitate the identification of suitable donors. Third objective is to define whether antibodies against non-HLA targets on the donor endothelium affect the results of transplants in highly sensitized patients. The aims of this collaborative project are fully compatible with those required for the program Health.2012.1.4-1. In objectives 2 and 3 two partners belonging to the SME sector of the European industry are involved.