NIHRDataInsights/HRCSData huggingface dataset:
Title: Can we treat genetic blood disorders by transplantation of stem cells to the fetus?
Funder: SPARKS

Abstract: Thalassaemia is a genetic blood disease that causes life-threatening anaemia in infants. Blood stem cell transplantation cures the disease but is successful for only 30% of patients. The remainder rely on blood transfusions that cause complications and early death. Transplantation of stem cells in the womb can cure genetic immunodeficiency disease. I will study whether blood stem cells found in the amniotic fluid around fetuses can cure thalassaemia. The abnormal gene that causes thalassaemia will be corrected using gene therapy. Corrected amniotic fluid blood stem cells will then be transplanted into a fetal model that have thalassaemia to test disease cure.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Optimisation of human iPS cell-derived platelet manufacture
Funder: Innovate UK

Abstract: Platelets are an essential component of blood, involved in homeostasis, clotting and wound healing. Certain medical treatments (esp. chemotherapy) cause a severe reduction in platelet count leading to uncontrolled bleeding. This can be treated with transfusions of platelets isolated from donor blood, but in approximately 15% of patients, repeated challenge with platelets from other donors causes an immune response, leading to 'alloimmune platelet refractoriness' which is costly to treat and life threatening. We have developed a method of producing platelets from stem cells (which can be made from the patient's own cells) and wish to develop this as therapy for low platelet count due to alloimmune refractoriness. This project is to scope the feasibility of upscaling the manufacturing process and reduce costs by up to 500-fold though process optimisation and use of proprietary small molecules that specifically modulate hematopoiesis and improve efficiency.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Evaluation of an antibody that inhibits thrombosis without causing bleeding
Funder: Innovate UK

Abstract: Thrombosis remains a major cause of death and morbidity worldwide. Existing antithrombotics reduce clotting but also increase bleeding, limiting their use. No agents approved for marketing or in clinical trials have been shown to significantly dissociate this bleeding risk from the degree of antithrombosis. This project relates to the initial manufacture and pre-clinical assessment of ichorcumab, a monoclonal antibody against the exosite 1 region of thrombin that is based on an antibody serendipitously discovered in a patient found to be completely anticoagulated but with no observed increase in bleeding risk - the ideal clinical profile. Ichorcumab has the potential to be the first drug to deliver antithrombosis without bleeding, making antithrombosis safer and more effective, and extending antithrombosis to new indications.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Demonstrating Feasibility of a Novel Diagnostic for Thrombosis Risk
Funder: Innovate UK

Abstract: This project will demonstrate the feasibility of applying a sophisticated analysis method for the detection of clinically relevant blood clotting defects in patients to an emerging diagnostic sensor platform technology that can be applied to improve outcomes in many high mortality conditions, particularly common amongst the ageing population. Thrombotic disorders are top causes for death, either as disease states – myocardial infarction or ischemic stroke, or as potential complications to most in-hospital treatments, including childbirth and routine surgery. The project will focus on demonstrating clear health benefits and attractive business case through the application of novel diagnostic techniques and will be delivered by Highland Biosciences, a micro SME that leverages a strong network of collaborators proven to deliver successful TSB funded projects.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD
Title: Creating an effective and non toxic blood substitute
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Blood transfusion is a life saving technology. However red blood cells: have a limited shelf life; need blood group typing; cannot be used in immune compromised individuals; are not available at the scenes of accidents, battlefields or major emergencies; and are susceptible to viral contamination. Blood transfusion is big business. In the UK alone two million units of blood are transfused annually at a cost of > £200 million. The addressable future global market value is $10Bn. A number of companies have attempted to develop alternatives to transfusions based on modifications of the red cell oxygen transport protein hemoglobin. However, toxic side effects have been seen in clinical trials. Arising out of BBSRC funded grants, the University of Essex has engineered novel hemoglobin molecules designed to reduce cell damage. A patent is pending. The purpose of this grant is to undertake lead optimisation, product development and in vivo testing on this next generation blood substitute.


Research activity codes: 5.4 SURGERY
Health categories: BLOOD
Title: Influence of anaemia on clot structure
Funder: Chief Scientist Office (Scotland)

Abstract: Thrombosis is a leading cause of morbidity in a wide range of anaemias, including acquired and congenital haemolytic anaemias[1-10] and anaemic patients with essential thrombocythaemia (ET)[11] and myelofibrosis[12]. The prothrombotic profile in these conditions is multifactorial, however a direct pathogenic role through abnormal clot structure has not been investigated. Epidemiological studies directly link premature coronary artery disease, arterial and venous thrombosis with compact or dense fibrin clot structure[13-18].The structure of the fibrin network such as fibre thickness, density and pore size contribute to mechanical stability and resistance of blood clots to fibrinolytic degradation. Our preliminary studies, involving ex-vivo manipulation of haematocrit in healthy volunteers, demonstrated shorter clot formation time, increased clot firmness and a slower rate of fibrinolysis at low haematocrits. The main objective of this PhD is to test the hypothesis that a difference in clot structure and stability exists between anaemic patients compared to non-anaemic controls. Additional outcomes are to examine changes to clot structure when these groups of patients receive blood transfusion or antiplatelet therapy. Patients with haemolytic anaemia and anaemic patients with ET and myelofibrosis along with the majority of controls will be recruited from Aberdeen Royal Infirmary. Citrated blood will be collected from volunteers to perform thromboelastometry, thrombin generation assay, thrombus lysis assay, flow cytometry, confocal microscopy and fibrin permeation. The expected outcomes are that patients with anaemia will demonstrate increased procoagulability resulting in shorter clot formation times, and a denser mechanically stronger clot structure that is more resistant to lysis compared to non-anaemic controls.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: Development of outcome tools and an evaluation pathway to monitor clinical progression in young boys with haemophilia
Funder: Department of Health (England)

Abstract: Haemophilia is an inherited disorder characterised by recurrent bleeding into joints, leading to irreversible joint disease and painful deformity. Prophylactic treatment with missing coagulation factors at an estimated cost per child of £100,000 per annum, has significantly reduced, but not alleviated all joint bleeding. During my doctoral research we have shown haemophilic children have smaller, weaker muscles and walk differently when compared to their healthy peers but these abnormalities were not detected with current clinical haemophilia-specific outcome tools. Using quantitative and qualitative methodologies, the aim of this research is to develop a robust package of clinical outcome tools for young children with haemophilia suitable for use in clinical and research settings and to enable clinicians to map an evaluation pathway for effective clinical decision making and early identification of children within this group of high cost patients who are at risk to go on and develop long term joint dysfunction.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD
Title: Expanding the limits of biomolecular simulations: revealing the mechanisms of blood clot formation using Fluctuating Finite Element Analysis.
Funder: Engineering and Physical Sciences Research Council

Abstract: Computational simulation of biomolecules has proven to be a very useful approach during the past few decades, and is now considered essential in broad range of disciplines ranging from the molecular understanding of life to drug discovery. Molecular dynamics is so frequently used to calculate the dynamic behaviour of proteins at the atomistic level firstly due to the large number of protein crystal structures that are publicly available in the Protein Data Base, but also because this methodology is well established, and excellent software packages are freely available to the academic biomolecular sciences community. However, we are still far from simulating cellular dimensions and time scales of entire biological processes. This will not be solved by hardware improvements in the foreseeable future, especially as the continuous increase in computational power is slowing and may come to an end. As a consequence, new methodologies are needed to reach longer time- and length-scales. This fellowship proposes to join two cutting edge methodologies in coarse-grained protein modelling to overcome this situation. Specifically, I will work with the Fluctuating Finite Element Analysis that models proteins as a non-rigid continuum subjected to thermal fluctuations, and the Multi-Scale Coarse-Graining method that aims to describe simplified molecular interactions using a physically-based bottom-up approach. Once this methodology is ready, I will implement it within a scalable piece of software suitable for High Performance Computing, and will use this new tool to simulate the fibrin network self-assembly process, one of the key events in clot formation. This is a highly important biological system, as in vivo imbalance is related to a number of human pathologies, including heart and brain infarction. Structural data on the clot architecture has been shown to correlate with clinical data on cardiovascular diseases. I will use currently available experimental data to demonstrate the capabilities of the proposed methodology and software. Next, further simulations will shed light on association pathways and affinities leading to fibrin polymerisation, on the process of lateral aggregation of protofibrils, on the role of each of the known interaction sites, on the influence of the external flow, and on the effect that some pathological mutants have on the self-assembly process and the final structure of the clot. Full accomplishment of these objectives will result in significant advances in biomolecular modelling methodology, together with the release of a general purpose application for biomolecular simulations on the mesoscale, and medically relevant results on the clot formation process and structure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: BLOOD
Title: Preclinical evaluation of rAAV encoding a novel highly expressed Factor VIII molecule for haemophilia A gene therapy
Funder: Medical Research Council

Abstract: The goal of this proposal is to generate sufficient data to support a Phase I/II gene therapy trial for haemophilia A (HA), the most common inherited bleeding disorder that results from mutations in the human factor VIII (hFVIII) gene. We have already developed a new gene therapy approach for a related bleeding disorder, haemophilia B, with a recombinant adeno-associated virus (rAAV) vector, which is currently being evaluated in a clinical trial. This experience will be used to facilitate the clinical transition of a novel, more potent human factor VIII (codop-hFVIII) molecule that overcomes the poor expression of the wild type FVIII gene. A single administration of a rAAV vector encoding codop-FVIII leads to supraphysiological FVIII levels without toxicity in mice. This level of expression is at least 400-fold greater than required for therapeutic efficacy (0.05IU/ml). Further evaluation of this promising approach is now being proposed in a context relevant to humans.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: The HAEM (Haemorrhage and Antifibrinolytics in Emergency Medicine) Project.
Funder: Department of Health (England)

Abstract: Sudden severe bleeding is an important medical problem in the UK and world-wide. Bleeding into the brain after head injury can kill or disable. Some diseases of the digestive system can cause life threatening bleeding and every year tens of thousands of women in developing countries die from severe bleeding after childbirth. Recent results from a large international clinical trial in bleeding accident victims show that a cheap drug called tranexamic acid reduces the chances of dying from the injuries and improves other patient outcomes without any increase in side effects. Tranexamic acid is not a new drug. It has been used to control bleeding during major surgical operations for many years. The realisation that this drug could be used to treat a much wider range of bleeding conditions holds the promise of important benefits for patients at low cost. The research team responsible for the accident victim research now want to conduct trials to see if this drug improves outcome in other types of serious bleeding. They are experienced in carrying out this sort of research and have an established network of doctors from all around the world that will be able to answer these important medical questions.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Oral iron, intravenous iron or discontinuation of therapy for older adults with treatment-unresponsive iron deficiency anaemia - a pilot randomised control trial
Funder: Chief Scientist Office, Scotland

Abstract: Anaemia due to low iron levels is common in older people and can cause tiredness and breathlessness. It is commonly treated with iron tablets. However, iron tablets do not improve anaemia in many people and they have side effects. We do not know what strategy of care is best for patients who do not respond to iron tablets: should we stop treatment, continue with tablets (which is current practice) or switch to iron given by a drip (intravenous iron)? We will conduct a pilot randomised controlled trial to compare these three strategies of care. We will recruit 84 older people with iron deficiency anaemia who are not improving on iron tablets, and randomise them to receive one of the above three strategies of care for three months. Key outcomes will include: how long it takes to recruit enough people to the trial, which method(s) of recruitment (clinic, adverts or GP letters) is/are most efficient, and the improvement in haemoglobin level (a measure of anaemia) in each treatment arm. The results will allow us to plan a large, multicentre trial to find out which of the three options should become routine clinical care in this situation.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Nuclear organisation and erythropoiesis
Funder: Medical Research Council

Abstract: The organisation of chromatin within the nucleus has a key role to play in the processes of transcription and replication but the mechanisms governing how chromatin domains are established and altered during the course of development and differentiation remain poorly understood. There is a broad consensus that chromatin is organised in dynamic loops but many questions remain about what may drive their formation, how long they are stable for and how they may alter with the cell cycle. The  globin gene region is one of the best-characterised segments of the genome and it is an ideal model with which to investigate such issues. Analysis of single cells will be an essential complement to the genome-wide studies of chromatin configurations described in Professors Higgs & Gibbons’ programme. Our ultimate aim is to gain better insight into transcriptional regulation. The questions we plan to address are – What are the kinetics of transcription from the  globin and nearby genes during erythroid differentiation? What are the concurrent spatial relationships across the  globin regulatory region? What mechanisms underlie the striking decompaction of chromatin around these heavily transcribed genes? What contribution may replication make to gene regulation and also to misregulation in disease?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Gene regulation by distal regulatory elements in Erythropoiesis and the effect of natural sequence variants.
Funder: Medical Research Council

Abstract: It has become clear over the last 10 years that control of gene expression is very often not determined by the promoter of the gene, but rather by variable numbers of regulatory elements, which are unpredictably distributed in and around the genes themselves. These so called distal regulatory elements are situate away from the genes the control, often over large genomic distances and are separated by intervening unrelated genes or even embedded in the introns of other genes. The inability to link any given gene with its regulatory elements is a fundamental problem which has greatly hampered our understanding of gene regulation. Although of great biological importance, the role of these elements in health and disease is becoming increasing clear as the effect of mutations in these regions begins to come to light. In particular the vast majority of predicted variants in the normal population, which from GWAS studies, are associated with disease susceptibility are not found in coding regions and are thought to be acting through changes in distal regulatory elements. To address this problem have developed a high resolution and high throughput method to robustly map the physical interactions between genes and their regulatory elements. Using this Capture-C method we have mapped en masse the regulatory interactions of over 450 genes in the mouse erythroid system. The Capture-C method massively increases the number of genes with linked regulatory elements and we intend to use this ability to study how the molecular events at regulatory elements coordinate expression from linked gene promoters. Our experimental model is the extremely well characterised murine erythroid differentiation system. This model provides large numbers of cells from well defined stages of differentiation which will allow us to study the transcriptional regulation of these genes in a dynamic fashion and includes two extremely well studied paradigms of gene regulation, the  and  globin loci. To study changes in protein binding we use high-resolution versions of the DNAse-seq and ChIP-seq assays and to determine the expression status of the genes under study we have developed highly quantitative RNA assays using metabolic labelling of nascent RNA. Additionally we will use our human erythroid model to investigate the effect of previously characterised GWAS SNPs responsible for normal variation of erythroid parameters to determine the underlying principals of how regulatory variants can affect human health and disease susceptibility.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Modernising the diagnosis of mucocutaneous bleeding disorders: next generation sequencing of novel loci associated with platelet dysfunction.
Funder: Medical Research Council

Abstract: Some mucocutaneous bleeding disorders such as von Willebrand disease and the major platelet disorders such as Glanzmann's thrombasthenia are well defined. However the majority of cases are due to undefined causes. Current investigation algorithms lack sufficient sensitivity and specificity to achieve specific diagnoses in these patients. In this proposal I suggest that this can be achieved more completely, more efficiently and more cheaply by a genomic rather than functional approach. Moreover the genomic approach will reveal links with other disorders and phenotypes in other specialties not seen with functional analyses. It will also directly indicate novel targets for therapy at a molecular level. Next generation sequencing (NGST) was introduced in 2009 (Nature 2010;467 1061-73) and by 2013 the exome of at least 20,000, and the entire genome of 4000, individuals, will have been analysed by the Sanger Institute and the Cambridge BRC. This exhaustive catalogue of sequence variants can be utilised for the benefit of patients suffering from inherited or de novo mutations underlying bleeding disorders. We and others have already shown that the genetic basis of a hitherto unresolved clinical condition can be identified with relative ease by sequencing the exome of a relative small number of unrelated cases. Many disorders will be more complex and more challenging but will benefit from our collaboration with the European Bioinformatics Institute supporting our current megakaryocyte/platelet pathway network of about 800 nodes and over a 1000 edges and from our award to fully functionally annotate the genome of all blood cells and their precursors as part of the International Human Epigenome Consortium. The clinical base and enormous genomic resources ensure the success of this project and that putative causative mutations will be identified for the functional studies in the final phase of the project which therefore offers an unparalleled novel training opportunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD