NIHRDataInsights/HRCSHealthCategories
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The dataset generation failed because of a cast error
Error code: DatasetGenerationCastError
Exception: DatasetGenerationCastError
Message: An error occurred while generating the dataset
All the data files must have the same columns, but at some point there are 1 new columns ({'HRCS2022_ID'}) and 1 missing columns ({'ID'}).
This happened while the csv dataset builder was generating data using
hf://datasets/NIHRDataInsights/HRCSData/hrcs_test_data.csv (at revision edd523a407fae44691f0b1154fb4b58d928bb1e4), [/tmp/hf-datasets-cache/medium/datasets/89507764079794-config-parquet-and-info-NIHRDataInsights-HRCSData-d0a3e006/hub/datasets--NIHRDataInsights--HRCSData/snapshots/edd523a407fae44691f0b1154fb4b58d928bb1e4/hrcs_test_data.csv (origin=hf://datasets/NIHRDataInsights/HRCSData@edd523a407fae44691f0b1154fb4b58d928bb1e4/hrcs_test_data.csv)]
Please either edit the data files to have matching columns, or separate them into different configurations (see docs at https://hf.co/docs/hub/datasets-manual-configuration#multiple-configurations)
Traceback: Traceback (most recent call last):
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1887, in _prepare_split_single
writer.write_table(table)
File "/usr/local/lib/python3.12/site-packages/datasets/arrow_writer.py", line 675, in write_table
pa_table = table_cast(pa_table, self._schema)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 2272, in table_cast
return cast_table_to_schema(table, schema)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 2218, in cast_table_to_schema
raise CastError(
datasets.table.CastError: Couldn't cast
HRCS2022_ID: string
FundingOrganisation: string
FunderAcronym: string
AwardTitle: string
AwardAbstract: string
AwardLayAbstract: string
RACs: string
HCs: string
-- schema metadata --
pandas: '{"index_columns": [{"kind": "range", "name": null, "start": 0, "' + 1239
to
{'FundingOrganisation': Value('string'), 'FunderAcronym': Value('string'), 'AwardTitle': Value('string'), 'AwardAbstract': Value('string'), 'AwardLayAbstract': Value('string'), 'ID': Value('string'), 'RACs': Value('string'), 'HCs': Value('string')}
because column names don't match
During handling of the above exception, another exception occurred:
Traceback (most recent call last):
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 1347, in compute_config_parquet_and_info_response
parquet_operations = convert_to_parquet(builder)
^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 980, in convert_to_parquet
builder.download_and_prepare(
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 884, in download_and_prepare
self._download_and_prepare(
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 947, in _download_and_prepare
self._prepare_split(split_generator, **prepare_split_kwargs)
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1736, in _prepare_split
for job_id, done, content in self._prepare_split_single(
^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1889, in _prepare_split_single
raise DatasetGenerationCastError.from_cast_error(
datasets.exceptions.DatasetGenerationCastError: An error occurred while generating the dataset
All the data files must have the same columns, but at some point there are 1 new columns ({'HRCS2022_ID'}) and 1 missing columns ({'ID'}).
This happened while the csv dataset builder was generating data using
hf://datasets/NIHRDataInsights/HRCSData/hrcs_test_data.csv (at revision edd523a407fae44691f0b1154fb4b58d928bb1e4), [/tmp/hf-datasets-cache/medium/datasets/89507764079794-config-parquet-and-info-NIHRDataInsights-HRCSData-d0a3e006/hub/datasets--NIHRDataInsights--HRCSData/snapshots/edd523a407fae44691f0b1154fb4b58d928bb1e4/hrcs_test_data.csv (origin=hf://datasets/NIHRDataInsights/HRCSData@edd523a407fae44691f0b1154fb4b58d928bb1e4/hrcs_test_data.csv)]
Please either edit the data files to have matching columns, or separate them into different configurations (see docs at https://hf.co/docs/hub/datasets-manual-configuration#multiple-configurations)Need help to make the dataset viewer work? Make sure to review how to configure the dataset viewer, and open a discussion for direct support.
FundingOrganisation string | FunderAcronym string | AwardTitle string | AwardAbstract string | AwardLayAbstract null | ID string | RACs string | HCs string |
|---|---|---|---|---|---|---|---|
SPARKS | null | Can we treat genetic blood disorders by transplantation of stem cells to the fetus? | 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. | null | 12WTUCL02 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Innovate UK | IUK | Optimisation of human iPS cell-derived platelet manufacture | 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. | null | 38053-276164 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Innovate UK | IUK | Evaluation of an antibody that inhibits thrombosis without causing bleeding | 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. | null | 39858-275214 | 5.1 PHARMACEUTICALS | BLOOD |
Innovate UK | IUK | Demonstrating Feasibility of a Novel Diagnostic for Thrombosis Risk | 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. | null | 41192-276328 | 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES | BLOOD |
Biotechnology and Biological Sciences Research Council | BBSRC | Creating an effective and non toxic blood substitute | 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. | null | BB/L004232/1 | 5.4 SURGERY | BLOOD |
Chief Scientist Office (Scotland) | CSO | Influence of anaemia on clot structure | 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. | null | CAF/14/04 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Department of Health (England) | NIHR | Development of outcome tools and an evaluation pathway to monitor clinical progression in young boys with haemophilia | 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. | null | CAT/CL10/008 | 8.1 ORGANISATION AND DELIVERY OF SERVICES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES | BLOOD |
Engineering and Physical Sciences Research Council | EPSRC | EPSRC Healthcare Impact Partnership for new blood clotting diagnostics and management | We propose to establish a Healthcare Impact Partnership for research which is stimulated by an unmet clinical need for improved monitoring and prediction of abnormal clotting responses to therapy or disease. Thromboembolic disease and associated blood clotting abnormalities cause significant morbidity and mortality in Western society, with stroke being the third-leading cause of death in the UK. Clotting abnormalities are responsible for thousands of preventable deaths annually inside UK hospitals and increasing numbers of NHS outpatients require monitoring of oral anticoagulant therapy (e.g. warfarin). But correlation of standard clotting tests to clinical outcome has been unsatisfactory, with uncertain healthcare benefits and limited clinical utility in terms of informing responses to ongoing treatment or disease progression. We wish to overcome these shortcomings by exploiting our advances in nanotechnology and clot detection. They provide the basis of a new way of monitoring, assessing and predicting the key microstructural and mechanical properties of fully-formed clots, based on information acquired within a few minutes in near-patient tests on small samples of blood. The fully-formed clot's microstructure determines its mechanical strength (hence ability to prevent bleeding) and its resistance to breakdown and dispersal by the body. Abnormalities in these properties are linked to significant health risks. Our discovery of the fractal microstructure of incipient ('infant') clots and its role in templating fully-formed ('mature') clots provides the basis of our proposal. We have established its feasibility through advanced imaging and analysis of model (fibrin-thrombin) clots. We now need to do this in therapeutically and pathologically modified blood. But our previous imaging techniques are not suitable for blood and we plan a new approach. Our work on nanoparticle fluorescence has established advanced identification/tracking techniques and we have implemented them to study biological cells. We plan to translate these approaches to analyse abnormal microstructure development in blood clots. The concept is based on interrogating nanoscale moving light displays (clusters of light), formed by fluorescent nanoparticles loaded into blood samples. An exciting aspect involves analysing clot deformation in response to stress. The light arrays provide a binary map of points delimiting clot structure and reporting deformation. We anticipate that this concept will provide a 'world-first' in yielding linked microstructural and mechanical properties of evolving clots, in the same measurement. The improved monitoring, assessment and prediction capabilities arising from this work will underpin (i) improved monitoring of clotting responses to anticoagulant and/or antiplatelet (e.g. aspirin) therapies; (ii) improved predictions of clot breakdown in response to therapy; (iii) improved dose response assessments of these treatments, and (iv) a basis for abnormal clot screening in patients who, while taking warfarin, suffer recurrent deep vein thrombosis or pulmonary embolism while appearing adequately anticoagulated in terms of present tests (INR). Our Healthcare Impact Partnership will provide the framework for collaboration between (i) experts in nanotechnological aspects of devices, imaging and analysis of biosystems; (ii) industrial partners with expertise in medical devices and microfabrication; and (iii) the Haemostasis Biomedical Research Unit (HBRU) at ABMU NHS Trust Hospital Morriston Swansea. The HBRU, with its expert clinical scientists and NHS Consultant colleagues, provides the clinically-facing focus for our studies, and their translation. Our industrial partners bring expertise which we foresee will underpin the development of technologies for near-patient tests both inside and outside hospital care settings. | null | EP/L024799/1 | 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES | BLOOD |
Engineering and Physical Sciences Research Council | EPSRC | Expanding the limits of biomolecular simulations: revealing the mechanisms of blood clot formation using Fluctuating Finite Element Analysis. | 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. | null | EP/M004228/1 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS | BLOOD |
Medical Research Council | MRC | Preclinical evaluation of rAAV encoding a novel highly expressed Factor VIII molecule for haemophilia A gene therapy | 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. | null | G0902219/1 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Department of Health (England) | NIHR | The HAEM (Haemorrhage and Antifibrinolytics in Emergency Medicine) Project. | 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. | null | HICF-0510-007 | 6.1 PHARMACEUTICALS | BLOOD |
Chief Scientist Office, Scotland | CSO | Oral iron, intravenous iron or discontinuation of therapy for older adults with treatment-unresponsive iron deficiency anaemia - a pilot randomised control trial | 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. | null | HRCS2018_04490 | 6.1 PHARMACEUTICALS | BLOOD |
Economic and Social Research Council | ESRC | Inherited blood disorders, globalisation and the promise of genomics: An Indian case-study | Sickle cell and thalassaemia, forms of inherited blood disorders (IBD), classified by the WHO under 'prevention and management of inherited birth defects', have recently been defined as an emergent global health crisis. The pattern of recessive inheritance implies that babies who inherit two copies of a mutant gene (from both parents) will have a serious blood disorder, needing long term treatment and care; while carriers who inherit only one copy will not have the disease. A much higher incidence poses significant healthcare challenges in low and middle income countries, especially sub-Saharan Africa and India. India is estimated to have the largest number of carriers of IBD in the world, around 42-45 million; where approximately 22,500- 37,000 babies with IBD are born each year. A significant proportion are born in households with little or no access to healthcare, especially in the rural, poor, marginalised ethnic and 'tribal' communities. Despite cheap diagnostic tests and treatments, including curative stem cell transplants, available across public and private sectors, only 5-10 percent of children receive optimal care in India. There is little research examining the social and ethical reverberations of carrier screening, especially of pregnant women, and the use of prenatal diagnosis and termination of affected foetuses, as preventive interventions as a means of 'prevention'. Further, it is imperative to examine how, given the widespread practice of sex selective abortions and poorly regulated markets, an appropriation of genetic technologies by state, public as well as private enterprise might further exacerbate existing structural inequalities related to ethnicity, caste, gender and disability. This 40 month long, Indian case-study will provide a comprehensive analysis of the social and ethical reverberations of policies and practices surrounding the treatment and 'prevention' of IBD, within the context of globalisation and the promise of genomics in reducing health inequities in the global South. The main aim of our research is to relate these global debates to local forms of engagement and therapeutic citizenship reflected in the practices of NGOs helping people (potentially) affected by these disorders in the rural, poor and marginalised communities. To contextualise our empirical work, we will first review literature from medical anthropology, sociology, global health policy and ethics to help refine the questions to be explored through a multi-sited ethnography. Fieldwork across four sites will involve main actor interviews, shadowing NGOs, community focus group discussions and practitioner interviews, as well as in-depth interviews with patients, carriers and two main carers in 80 households, from rural/semi urban poor areas and 10 households from a higher socio-economic, urban background. These households will be visited three times over 12-14 months. Researchers will use a topic guide for interviews on how IBD are recognised and treated, and decisions related to risk and long term care, and maintain health diaries for each family with a record of illnesses, health expenses and decisions related to health. The research will provide theoretical insights from medical anthropology/ sociology/ bioethics and the empirical findings to inform policy and practice on the far reaching social and ethical ramifications of the use of genomic technologies as a means of 'prevention' of recessive gene disorders in particular, and the intersections between genetics, ethnicity/ 'race', gender, kinship, disability and citizenship at a broader level across South Asia. Further, the project will provide methodological insights into a model of community engagement, where the local users and community organisations are intrinsic to the conception and execution of the research as well as the recommendations based on the research, to ensure that they have a stake and benefit from the dissemination plan. | null | HRCS2018_05272 | 4.3 INFLUENCES AND IMPACT | BLOOD |
Medical Research Council | MRC | Nuclear organisation and erythropoiesis | 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? | null | HRCS2018_10287 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Gene regulation by distal regulatory elements in Erythropoiesis and the effect of natural sequence variants. | 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. | null | HRCS2018_10291 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Modernising the diagnosis of mucocutaneous bleeding disorders: next generation sequencing of novel loci associated with platelet dysfunction. | 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. | null | HRCS2018_10438 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Transfusion and Treatment of severe Anaemia in African Children: a randomised controlled trial (TRACT) | TRACT is a multicentre randomised controlled trial to identify optimal transfusion strategies and supportive treatment for 3700 African children, aged 2 months to 12 years, presenting to hospital with severe anaemia (defined as haemoglobin (Hb) <6 g/dl). Children will be enrolled at admission to hospital over 2 years in Malawi and Uganda and followed for 6 months. The trial has been designed to address the poor outcome of this condition including high rates of in-hospital mortality, 6-month case fatality and chronic morbidity. Factors associated with poor outcome include potentially treatable co-morbidities such as recurrent infection and multiple vitamin deficiencies, which are not addressed in current guidelines. TRACT is designed to probe each of these multiple contributing factors directly. TRACT will simultaneously evaluate three ways to reduce short and longer-term mortality (primary endpoint) and morbidity following severe anaemia in Sub-Saharan Africa using a factorial design: 1/ Liberal transfusion (30ml/kg) versus conservative transfusion (20ml/kg) vs no transfusion (last strategy for children with Hb>4 g/dl and uncomplicated severe anaemia only) 2/ Multi-vitamin multi-mineral (MVMM) supplementation (including folate/iron) for 3 months versus routine care (folate/iron alone) 3/ cotrimoxazole prophylaxis for 3 months versus no antibiotic prophylaxis. The primary outcome is cumulative mortality to 4 weeks (transfusion comparisons) and to 6 months for the nutritional support/antibiotic prophylaxis comparison. Secondary outcomes include mortality at 48 hours, 4 weeks, 3 months and 6 months (cumulative) (where not the primary outcome); development of new profound anaemia (Hb<4g/dl) during acute admission or development of severe anaemia (Hb<6g/dl) post discharge; readmission to hospital; proportion achieving correction of anaemia (defined by WHO as Hb>9g/dl); adverse events relating to transfusion. | null | HRCS2018_10439 | 6.4 SURGERY | BLOOD |
Medical Research Council | MRC | Engineering a new generation of blood substitutes | There is a clinical need, and a financial market, for a long-lasting sterile red blood cell substitute to be used in environments or patient groups where homologous blood is not available or appropriate. Synthetic hemoglobin (Hb) is the best candidate for the oxygen-carrying component of a blood replacement. However, cell-free Hb displays an inherent toxicity relating to its capacity to induce oxidative reactions, causing damage to DNA and cell membranes. We have shown that tyrosine residues can enhance the safe removal of these oxidative intermediates through the formation of safe electron transfer pathways from the external environment of the protein to the heme iron. We have patents pending on novel bioengineered Hb mutants with additional electron pathways resulting in rapid and safe removal of toxic intermediates. Furthermore, we recently discovered an intrinsically less reactive form of Hb that is a better starting molecule to engineer a safe product. The first aim is to generate new tyrosine mutants of this novel Hb species, optimising the ability of plasma reductants such as vitamin C to decrease oxidative toxicity as measured by cell free liposome studies and damage to primary aortic endothelial cells. (Milestone 1). Additional mutations, known to decrease NO scavenging at the heme oxygen binding site, will then be added. A lead candidate will emerge from this process and will then be converted into a candidate blood substitute via globin PEGylation to increase circulation time. We will upgrade protein production (Milestone 2) to a scale for testing in models of trauma and transfusion. Real time monitoring and ex vivo biochemistry will be undertaken to obtain the maximal amount of information from each study. Succesful tests in the model systems (Milestone 3) will greatly enhance our goal of securing further funding to further optimise our product for clinical trials. | null | HRCS2018_10663 | 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | MICA: An open label dose-escalation study of a novel adeno-associated viral vector for gene transfer in subjects with haemophilia A | The goal of this proposal is to conduct a Phase I/II gene therapy trial for haemophilia A (HA), the most common inherited bleeding disorder, which results from mutations in the human factor VIII (hFVIII) gene. The same serotype 8 pseudotyped adeno-associated virus vector (AAV8) that mediated stable (>3 years) therapeutic expression of transgenic protein without long-lasting toxicity in subjects with haemophilia B (HB), a related condition, will be used to evaluate a novel FVIII expression cassette: HLP-codop-hFVIII-V3. This expression cassette (5.2kb) has been engineered so that it is efficiently packaged into AAV8 virions, despite being larger than the normal packaging capacity of this vector (4.6kb). Extensive testing in animals showed that in the context of AAV8 this oversized hFVIII cassette was at least 20X more potent than vectors encoding wild-type FVIII. Importantly, AAV8 HLP-codop-hFVIII-V3 had an excellent safety profile even at doses that were 10X higher than planned for use in clinical studies. A first in man, Phase I/II dose escalation study of the oversized hFVIII expression cassette is now proposed in adults with severe HA. The primary objective is to establish the safety and efficacy of systemic administration of AAV8-HLP-codop-hFVIII-V3 vector over three different dosage levels: 2e11, 6e11 and 2e12 vector genomes/kg. This is the same dose range tested in the HB clinical trial. We therefore predict that systemic administration of the oversized hFVIII vector will be safe, with absence of persistent Grade III or greater dose-limiting toxicity (according to modified CTCAE v.4). The key secondary objective is to define the dose of vector that mediates expression of hFVIII at > 5% of normal in peripheral blood; a level that can significantly ameliorate the severe bleeding phenotype. Successful HA gene therapy will transform the treatment paradigm for this disease and impact on a variety of other disorders affecting the liver. | null | HRCS2018_10666 | 6.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | Recombinant proteins for GMP-compatible niche creation to optimize in vitro platelet production for human transfusion | WP1: Identification of candidate membrane-expressed proteins (MExPs) The secreted and membrane-tethered proteins for cell lines that support proplatelet (ProPt) formation by MKs in cocultures that promote have been identified from expression arrays and proteomics analysis. The ectodomain of 400 candidate proteins will be cloned into expression vectors by a gene synthesis company. WP2 Synthesis of recombinant (rec)MExPs. The recMExPs will be expressed in a mammalian system using the existing infrastructure of Dr Wright's laboratory (Sanger Institute). The recMExPs will be produced in two forms: a soluble pentamer for the initial screening (WP3) and a tagged monomer for immobilization onto a 2D/3D substrates (WP4). WP3: High throughput screening of candidates recMExPs. Phase I: ProPlt assay with single recMEXPs: Cultured MKs will be harvested and plated into fibrinogen-coated 96-well plates with pentameric recMExPs. ProPlt formation will be analyzed 48 hours later by means of immunohistochemistry and automated image analysis. Phase II: ProPlt assay using a combinatorial algorithm: Preliminary data have shown that concurrent recMExPs have a synergistic effect on ProPlt formation. A combinatorial screen of all positive recMExPs identified in Phase I will be carried out using an "overlapping blocks" mathematical model to identify the best combinations of 3 recMExPs. WP4 Immobilisation of candidate recMExPs onto substrates for niche creation. WP4 will validate the results obtained in WP3 with non-soluble immobilized forms of the same recMExPs. Monomeric recMExPs with a biotin tag will be immobilized on a plastic surface coated with fibrinogen and streptavidin in equimolar ratios. The ProPlt assay will be carried out on these functionalized plates as described above. We will also determine the range of optimum surface density for each recMExP by ELISA. Finally we will generate appropriately-tagged recMExPs for functionalisation of collagen-based 3D scaffolds. | null | HRCS2018_10756 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | ADAMTS13 structure and the molecular basis of VWF recognition and cleavage | Von Willebrand factor (VWF) is a large multimeric plasma glycoprotein that is critical for platelet recruitment to sites of blood vessel damage. VWF platelet-tethering function is highly dependent upon its multimeric size, with larger VWF multimers being more haemostatically competent. VWF plasma multimeric size, and consequently its platelet-tethering function, is regulated in the blood by proteolytic processing by the plasma metalloprotease, ADAMTS13. Deficiency in VWF causes the most common inherited bleeding disorder, whereas people with ADAMTS13 deficiency suffer from life-threatening thrombotic thrombocytopenic purpura. Increasing VWF and decreasing ADAMTS13 levels in plasma are risk factors for both myocardial infarction and stroke. ADAMTS13 is very highly specific as it cleaves only one known substrate protein, VWF, and does so at just a single site - between Tyr1605 and Met1606 in the VWF A2 domain. Physiologically, proteolysis can only occur when VWF is unravelled by shear as the scissile bond and cryptic exosites in VWF are only revealed when VWF unravels. The holy grail of research into ADAMTS13 and VWF is to understand the complex mechanism of VWF force-induced VWF unfolding and highly single substrate specific cleavage by ADAMTS13. To address this, we will express, purify and characterise a panel of ADAMTS13 domain fragments to understand their interaction with and proteolysis of VWF and the importance of Ca2+ binding in this process. We will also determine the crystal structures of these fragments, in isolation, in complex with anti-ADAMTS13 Fab fragments and in complex with VWF. The results from these studies will not only provide detailed information upon ADAMTS13 function, it will provide insight in to thrombotic disease, provide insight into the structure and function of other ADAMTS family members, and perhaps more importantly provide the opportunity to rationally modify/improve ADAMTS13 for use as a therapeutic agent. | null | HRCS2018_10862 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | The role of von Willebrand Factor in endothelial platelet capture | This study will use an in vitro system to study the role of VWF in platelet capture by endothelial cells(EC) and thus its role in atherogenesis. Epidemiological studies of patients with CVD or genetic defects of VWF addressing this have given conflicting results. Animal studies have been suggestive but again incomplete. A novel aspect of this proposal is the use of primary (progenitor) endothelial cells cultured from peripheral blood and mutant VWF. We previously showed that these cells synthesise, store and release VWF in a physiological manner and that they provide a unique demonstration of how defects in VWF synthesis affect the function and behavior of endothelial cells. Moreover, using state of the art perfusion systems and bespoke perfusion chambers with differing geometries we are able to reproduce the patterns of flow encountered in vivo and which appear to be a major determinant of plaque formation. Indeed a key theme throughout this study is the importance of shear in VWF biology: both for synthesis and for function. Variable distribution of VWF within the vascular tree in part reflects these differences in flow and is reflected in their different susceptibility to atheroma. This study will provide precise detail on this relationship and map VWF expression through narrowed and branching vessels where turbulent flow can produce large changes in shear over small distances. The critical measure in all cases will be platelet capture on the surface of the EC and a secondary measure will be evidence of resulting EC activation. In both cases the key question will be whether this is mediated by circulating VWF or by VWF emerging from the EC. Our experimental approach is designed specifically to give a precise answer to this question in a physiologically representative system, but also determine mechanisms and consequences for EC.The answers will be potentially crucial factors in planning to exploit the central position of VWF for therapeutic effect. | null | HRCS2018_10994 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Experimental manipulation of indices of lesion severity in multi-vessel coronary artery disease: Quantitative exploration of collateral influences. | Aims: To test the hypothesis that collateral mediated changes in coronary flow pattern can alter the physiological severity of stenoses in multi-vessel coronary artery disease. Objectives: -To understand how 'two-for-one' stenting occurs (how the severity of a stenosis can be improved without a need for further stenting or bypass surgery). -To quantify the role of the collateral circulation in this clinically important process. -To incorporate an assessment of collateral function into the physiological diagnostic approach to patients with multi-vessel disease. Methodology: -40 patients with multi-vessel CAD (30-40% of all CAD patients) will be recruited over 2.5 years. All angiography will be clinically indicated. -Patients will undergo baseline intracoronary pressure and velocity measurements using a 0.014" pressure and flow sensor tipped wire. Assessments will be made to all moderate-severe stenoses. -One wire will be placed in one vessel (A) and a second wire in another vessel (B). -An intracoronary balloon will be positioned over the wire in a proximal, non-diseased segment in (A). It will be inflated to low-pressure (to avoid endothelial damage) for 60-90 seconds to transiently occlude flow. Pressure and flow will be measured distally in (A). -Pressure and flow will be measured simultaneously in (B) to provide data on collateral flow modulation between (A) and (B). -Measurements during balloon occlusion will be compared to baseline to quantify flow redistribution in response to an acute change in antegrade flow in (A). -The process will be repeated with hyperaemia to determine FFR and changes from baseline. -Wave intensity analysis will be applied to determine the effect of hyperaemia on collaterals. Scientific and medical opportunities: Findings from this study will impact across the entire spectrum of the disease, with mechanistic insights that can be readily translated into improved clinical practice. | null | HRCS2018_10995 | 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES | BLOOD |
Medical Research Council | MRC | Mechanisms and functions of CRACR2A-L Rab GTPase in vascular endothelial cells | Objective 1: To determine the contribution of CRACR2A-L to Weibel Palade body trafficking. The general strategy for this project will be to use high resolution imaging to quantify and measure the distribution of CRACR2A-L and vWF in endothelial cells. Contribution of CRACR2A-L to Weibel Palade body trafficking in response to thrombotic stimuli will be assessed by overexpressing wtCRACR2A-L or GTP/Ca2+-binding mutants or alternatively, cellular levels of protein will be reduced by short interfering RNA. Secretion of vWF as a measure of Weibel Palade body exocytosis will be assayed using ELISA. The effect of CRACR2A-L on other endothelial functions such as apoptosis and proliferation will also be assessed. Objective 2: To discover the fundamental mechanisms by which CRACR2A-L regulates Weibel Palade bodies. Affinity chromatography followed by LC-MS/MS will be used to identify downstream effector proteins. Potential effector proteins will be identified and ranked according to peptide abundance and pathway analysis. Confirmed effectors will be verified by co-immunoprecipitation and rescue of function experiments using high resolution imaging. To be able to understand the structural mechanisms of CRACR2A-L action, structural models will be created by X-ray crystallography and homology modelling. Objective 3: To verify the in vivo role of CRACR2A-L using an endothelial specific knockout mouse. First, production of a CRACR2A global 'knockout first' (with conditional potential) mouse will be outsourced. Subsequent breeding with FLP deleters and endothelial specific Cre recombinase mice will generate an endothelial specific CRACR2A-L knockout mouse. The in vivo contribution of global and endothelial CRACR2A-L to Weibel-Palade body exocytosis will be analysed by measuring clotting in response to tail injury. In addition, real time intravital imaging of clot formation will be performed in the femoral artery and in the mouse ear. Angiogenesis will also be assessed. | null | HRCS2018_11118 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Hypoxic pre-conditioning of seeded tissue engineered scaffold to improve in vivo neovascularisation | Aim: To determine if hypoxic pre-conditioning of seeded decellularised trachea scaffold will promote the release of pro-angiogenic cytokines and accelerate angiogenesis. Objectives: 1. Optimising hypoxic pre-conditions - Determine if hypoxic preconditioning of seeded cells promotes pro-angiogenic factors which accelerates neoangiogenesis 2. Testing hypoxic pre-conditioning response in in vivo study - Using heterotopic transplant of seeded scaffolds on mice model to demonstrate accelerated functional angiogenesis in vivo Methodology: 1. Determine if hypoxic preconditioning enhances angiogenesis of seeded scaffolds by using CAM assay to delineate the best conditions 2. Perform cytokine analysis of conditioned medium to interrogate for pro-angiogenic factors 3. Ascertain functional characteristics of angiogenesis by using in vivo murine model for heterotopic transplant of scaffold accompanied by histological and SEM analysis of explanted scaffolds 4. Establish if a novel photoacoustic imaging technique can provide non-invasive analysis of microvasculature Scientific and medical opportunities: 1. Improve the understanding of angiogenesis process in implanted trachea scaffolds in vivo 2. Improve angiogenesis in seeded scaffolds by determining the right hypoxic environment for MSC production of pro-angiogenic factors 3. Potential amalgamation of this research with other on-going parallel research on optimisation of tissue engineered trachea in vivo which will facilitate the development of GMP grade scaffold for clinical use 4. Validation of the use of photoacoustic images to monitor angiogenesis in vivo will allow for reduction in the use of more invasive methods and possible pre-clinical applications | null | HRCS2018_11150 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | The genetic basis and biology of dyskeratosis congenita and bone marrow failure | Dyskeratosis congenita and bone marrow failure are a heterogeneous group of life threatening disorders affecting children and adults. They are unified by the inability of the bone marrow to make an adequate number of mature blood cells and patients die prematurely from infection or bleeding. We hold a large unique international registry of bone marrow failure patients, with samples stored from 643 patients with dyskeratosis congenita and 766 patients with bone marrow failure. In approximately 30% of these dyskeratosis congenita patients the genetic basis is unknown and in bone marrow failure patients the primary pathology remains unknown in over 80% of cases. The main aim of the research is to determine the genetic basis and primary pathophysiology of dyskeratosis congenita and bone marrow failure. To facilitate this goal we will undertake genetic analysis (principally based on next generation sequencing) in families we have collected with two or more affected individuals with bone marrow failure, but which do not meet the criteria of known bone marrow failure syndromes. Characterization of the familial forms of bone marrow failure will lead to the identification of new genes and biological pathways that are likely to be important in the idiopathic forms of these disorders. Elucidation of the genetic basis will provide new diagnostic and therapeutic strategies that are highly desirable since treatment remains unsatisfactory for many patients with bone marrow failure. | null | HRCS2018_11836 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Development of a novel therapy for Beta-Thalassaemia using CRISPR/Cas9 to edit the major alpha-globin enhancer | Beta-thalassaemia is an inherited anaemia caused by reduced or absent production of the haemoglobin component beta-globin. Despite being one of the first molecular diseases to have its pathophysiology characterised, the management of beta-thalassaemia is far from optimal, limited to supportive therapy for the majority. We know that the unbalanced production of globin chains and subsequent excess of alpha-globin chains are the central causative factors in the pathophysiology of this condition. Currently, most attempts to ameliorate beta-thalassaemia aim to resolve globin imbalance by increasing gamma-globin production. In this project we aim to take a complementary approach; the reduction of excess alpha-globin chains, as natural reductions of alpha-globin output, in the form of co-inherited alpha-thalassaemia, ameliorate the disease phenotype in beta-thalassaemia patients. To achieve this reduction, the major regulatory element controlling alpha-globin expression will be deleted using the CRISPR/Cas9 system. Proof-of-principle experiments have demonstrated the efficacy of this approach. We hope to develop the efficient editing of long term repopulating haematopoietic stem cells (LT-HSCs) and have two complimentary aims: 1) To optimise gene-editing of the MCS-R2 enhancer by identifying the key sequences that need to be disrupted to achieve the ideal level of alpha-globin knock-down. This will be done through generating a guide-RNA library to edit various transcription factor binding sites, using a newly developed Cas9 derivative that allows for flexibility in the PAM specificities required for CRISPR/Cas9 editing. 2) To identify which sub-population of stem cells have long-term repopulating ability. Evidence suggests that the CD49f+ fraction of CD34+ cells are enriched in LT-HSCs. We will use a xenograft mouse model to evaluate whether improved editing efficiency and long-term repopulation can be achieved by editing this purified CD49f+ sub-population alone. | null | HRCS2018_11863 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | Understanding granule disorders of myeloid cells by unravelling the interactome and function of the Nbeal2 protein | The regulation of myeloid cell secretory granules has a key role in atherogenesis and thrombosis. Understanding granule function could lead to new treatments for haemostatic and cardiovascular diseases. I will focus on NBEAL2 variants, which cause Gray Platelet Syndrome (GPS), a rare bleeding disorder. Molecular studies on cells from patients and knockout mice show Nbeal2 is key to PLT alpha-granule and NEU specific granule regulation and function. I will use iPSC technology and CRISPR genome editing to elucidate the mechanism by which NBEAL2 variants cause granule pathology. Preliminary proteomics studies of iMKs have identified 64 proteins interacting with Nbeal2. Hypothesis 1: GPS variants cause loss of function of one/several interactions with Nbeal2 I will introduce by CRISPR-editing the codons for GPS-causing BEACH-domain variants M2080K, P2100L and G2290W to generate mutants of the line IPSC-S4_NBEAL2_TAP for forward programming to iMKs in biological triplicates (Ghevaert lab protocol; transcription factors GATA-1, FLI-1, TAL-1; tetracycline inducible expression). I will characterise iMKs by ATAC- and RNA- seq, confocal and electron microscopy, platelet formation/function assays and perform pulldowns. Nbeal2's interactions will be defined through proteomics analysis by mass spectrometry (Lamond laboratory) and loss-of-interaction(s) will be confirmed by bi-directional immunoblots, co-localisation and proximity ligation assays. Hypothesis 2: Proteins in the Nbeal2 interactome have increased likelihood of being candidates for inherited blood cell disorders I will apply a new Bayesian algorithm to analyse genome sequencing data for ~750 unexplained BPD cases to determine if the 64 genes encoding Nbeal2's interactors are enriched for rare, possibly causal variants. I will verify putative candidate variants using control databases, detailed clinical phenotyping and co-segregation of pedigrees and functional studies using a CRISPR-knockout iPSC line. | null | HRCS2018_11871 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | IMPC: Analysis of the role of Cx57 in the regulation of platelet function, haemostasis and thrombosis | Platelets are small cells that control blood clotting. When they encounter cuts or damage to blood vessels they rapidly become sticky and stick to each other. This forms a plug, the first stage of clot formation that stops the bleeding as quickly as possible. Blood vessels become abnormal in cardiovascular disease and platelets can mistake these diseased vessels for cut vessels and consequently trigger the blood to form clots inside blood vessels (this is also known as thrombosis). This can clog up arteries and is the main trigger for heart attacks and strokes, which are frequently fatal. Scientists' successes in identifying how platelets sense healthy and damaged blood vessels, and also communicate with each other, has been critical in developing more effective drugs to prevent heart attacks and strokes, although such cardiovascular diseases still represent the principal causes of death in the UK. We are therefore focussing on increasing our understanding of the molecules and processes that enable platelets to be controlled in order to develop more effective medicines. We have recently found a new protein called Cx57 on platelets and have produced considerable data to show that this is likely to contribute to thrombosis. In order to confirm this we need to study platelets that do not have this protein. In this project we will use mice that have been genetically engineered to lack Cx57. We will test what effect this has on platelet function, bleeding and thrombosis. This will form an important step to determine whether drugs that target this protein may be successful in preventing thrombosis and the other diseases in which platelets are involved. | null | HRCS2018_11932 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES | BLOOD |
Medical Research Council | MRC | IMPC: Phenotyping Cardiovascular Development of Rbms1-null mice | The therapeutic stimulation of new blood vessel growth is considered a promising treatment for diseases in which organs become oxygen starved, for example after a heart attack or stroke and in diabetic vascular eye disease. Moreover, blood vessel function is thought to contribute to neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. However, we still have large gaps in our knowledge of how blood vessels normally grow to support the function of the brain, heart and other organs. Moreover, the first therapeutic attempts to stimulate vessel growth to alleviate oxygen starvation were ineffective, because the new vessels were not properly embedded into the organs they should supply. Based on prior work, we now know that two molecules called NRP1 and ITGB1 are essential to guide newly formed blood vessels to the right places in many organs. However, both molecules can also promote the formation of abnormal blood vessels and thereby exacerbate vascular problems in some diseases. Moreover, it is difficult to manipulate these molecules therapeutically, because they also participate in several other essential processes in the body. It is therefore important to identify additional molecules that function together with NRP1 and ITGB1 in blood vessel growth and may provide more selective targets for therapy. Our pilot studies suggest that a molecule termed RBMS1 functions together with NRP1 and ITGB1 in signalling pathways that support blood vessel growth. Moreover, mice lacking RBMS1 die before birth, demonstrating that its normal function is very important. However, very little is still known on the role of RBMS1 in normal cells, how it may support embryonic development and whether it plays a role in blood vessel growth by interacting with NRP1 and ITGB1 or in other pathways. We will therefore establish when during development RBMS1 deficiency causes death, determine which organ systems are affected and examine whether blood vessel growth is defective when RBMS1 is missing. | null | HRCS2018_11991 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Role of regulatory elements in the genetic determination of VWF level in Von Willebrand disease and healthy individuals | In the UK there are ~10,000 VWD patients and they mainly present with mucocutaneous bleeding. The ThromboGenomics (TG) high throughput sequencing (HTS) test, introduced as a diagnostic test in the NHS in 2015 identifies causal variants in VWF exons. There is an assumption, partially supported by TG test results that a fraction of VWF variants, labelled in reference databases as LPV and PV have been erroneously ascribed their label. Therefore, the fraction of type 1 VWD patients in whom a conclusive molecular diagnosis can be reached may be lower than the estimated 75%. I will use HTS to analyse the 0.5 MB comprising the VWF-CD9 genes in 1,000 VWD patients to identify LPVs in non-coding elements of the locus through comparison with data from 10,000 WGS-analysed controls from the INTERVAL RCT. I will perform a fine-mapping analysis to associate variants in the 0.5 MB and VWF levels. I will then use a new Bayesian algorithm to search for rare variants enriched in the 1,000 VWD patients using 42,000 INTERVAL and 100KGP controls. Erroneous assignment of pathogenicity status to variants will be minimised by having access to NHS record data of the WGS controls, in contrast to the anonymised whole exome sequenced (WES) samples from the ExAC Consortium. There is a considerable chance that a DNA variant present in a regulatory element of VWF and observed in a few or a single VWD patient(s) but absent from the 42,000 controls is not causal of VWD. So putative causal DNA variants will be verified for co-segregation in pedigrees. Those that co-segregate will be selected for functional validation. The variant will be introduced in iPSCs by CRISPR-Cas9. Wild-type and edited iPSCs will be forward programmed into ECs and MKs, in which I will measure VWF transcript and VWF protein levels. The genome-editing is relatively simple for insertions/deletions but challenging for single nucleotide variants. So as a back-up approach iPSC lines will be generated from the relevant patients. | null | HRCS2018_12095 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Development of highly sensitive methods for defining off target mutations to enable safe gene editing of haematopoietic cells for transplantation | Sites of off target CRISPR-Cas9 nuclease activity will initially be defined in purified genomic DNA. Digenome-seq shows that RGEN cleavage in vitro is a good predictor of off target sites but it uses whole genome sequencing to identify cut sites, making it prohibitively expensive and insensitive. The novel method involves ligating a customized sequencing adaptor to RGEN cut sites to allow them to be specifically sequenced. I have previously developed oligonucleotide capture technology for extremely deep sequencing (>100,000 fold coverage). Biotinylated oligonucleotides will be designed to pull down all of the potential sites of Cas9 cleavage identified in vitro and these will then be used to define with high sensitivity whether off target mutations occur during in vivo editing of primary cells. In addition oligonucleotides will be designed to the viral vector and the sequences to be inserted by HDR so that off target sits of integration can be identified. I plan to investigate whether a chromosome conformation capture based method (Capture-C) I pioneered, can improve the sensitivity of the assay detect to sites of off target integration. Off target effects will be studied in two models of genome editing for the treatment of thalassaemia and sickle cell disease. The first model has been developed in the host laboratory to treat HbE beta thalassemia and uses a single CRISPR-Cas9 cut and the non homologous end joining pathway to delete key transcription factor binding sites at the main enhancer of the alpha globin gene. A previously published method will also be set up, which uses homologous recombination to correct the beta globin gene in situ and simultaneously insert a cell surface marker for purification of corrected cells. This uses an adeno-associated virus (AAV) 6 vector to deliver the template for HDR and I plan to use a second AAV-6 vector to deliver Cas9 controlled by an inducible promoter to study how Cas9 expression alters off target effects. | null | HRCS2018_12191 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | Molecular mechanism by which the E325K mutation of human KLF1 causes a severe dyserythropoietic anemia, utilising a novel model system of RBC disease | KLF1 is an erythroid specific transcription factor essential for erythropoiesis. In recent years the number of individuals identified with disease phenotypes mapped to KLF1 mutations has increased rapidly. Of these the most severe, a form of dyserythropoietic anemia, is causally linked with the monoallelic mutation E325K; the effect of this mutation more severe than monoallelic loss of function KLF1 mutations. However, how the mutation affects the function of KLF1 in vivo resulting in a dominant phenotype is not known. Studying the molecular defects behind many RBC diseases is severely impeded by paucity of suitable and adequate quantities of material from anemic patients. We have recently developed technology and generated the first human immortalized adult erythroid lines, which recapitulate erythropoiesis, and provide a sustainable supply of cells. We have also developed a platform for CRISPR-Cas9 genome editing of these lines. We will use these technologies to create model disease cellular systems, generating a line from a patient with the E325K mutation, and introducing the mutation into an existing line. These systems will be used to (i) obtain a comprehensive map of the complete repertoire of proteins aberrantly expressed in cells expressing E325K KLF1 by comparative proteomics (ii) delineate molecular mechanisms by which the E325K mutation results in disrupted gene regulation, specifically determining if E325K KLF1 exhibits altered DNA binding specificity in vivo and if it interferes with the occupancy rate of wild type KLF1 at gene regulatory regions by ChIP-seq, and how E325K KLF1 then distorts the genetic readout of cells via analysis of chromatin configuration at gene loci required for interaction of regulatory elements and thus regulated gene expression using Capture-C 3C (iii) whether the mutation perturbs KLF1-co-factor binding required for such interactions. The data will also provide further insight into KLF1-directed transcriptional control. | null | HRCS2018_12211 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | How do mutations in non-muscle myosin 2A cause bleeding disorders and other defects? | Over 80 mutations in MYH9 have been described (Human Genome Mutation Database) that collectively cause an autosomal-dominant disorder known as MYH9 disease. MYH9 encodes non-muscle myosin 2A (NM2A). In humans, the outcomes of this disease range from mild to life-threatening. Symptoms include clotting disorders in which platelets are enlarged and bleeding time is prolonged (thrombocytopaenias), aggregation of NM2A in neutrophils, cataracts, deafness and glomerulosclerosis (which can be lethal). In platelets and other non-muscle cells, NM2A is found both as an inactive compact folded molecule, known as '10S' (based on its sedimentation coefficient), and as an active extended molecule (6S) which forms filaments of 20-30 molecules. In the 10S form, the coiled coil tail wraps around one of the motor domains, and this motor-tail interaction is important in stabilising the inactive state. Plotting the mutations onto a model of the folded molecule, together with our preliminary data, suggest that a significant number of mutations are likely to interfere with this interaction, destabilising the inactive state, which would result in premature filament formation, affecting cell contractility, and thus explain why these mutations result in MYH9 disorders. Our goal is to test this hypothesis by a combination of approaches, from investigating the effects of mutations on filament formation in cells, to investigating the effects of mutations on the secondary structure of the coiled coil, and, by using cryo-EM to obtain a detailed high resolution structure of the folded molecule, to precisely define how the tail interacts with the motor, and thus understand how mutations could disrupt this interaction. | null | HRCS2018_12214 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Evaluation of the role of ARAP1 in platelet function and thrombosis | Platelets are small cells in the blood that are essential for hemostasis, but can also contribute to thrombosis and cardiovascular disease when activated inappropriately. We have previously shown that platelet hyperactivity can contribute to resistance to anti-platelet therapy, potentially increasing the risk of stroke and myocardial infarction in patients with cardiovascular disease receiving anti platelet therapy. One of the main intracellular signalling kinases that contributes to platelet hyperactivity is the lipid kinase PI3kinase, which phosphorylates lipids such as PI(4,5)P2 in the membrane resulting in the generation of PI(3,4,5)P3. The mechanism by which PI3 kinase increases platelet function is still largely unknown but it likely to be mediated though binding of proteins to PI(3,4,5)P3. We recently showed that one of the proteins that binds to PI(3,4,5)P3, and therefore may contribute to platelet hyperactivity, is the Arf and Rho GTPase activating protein ARAP1. Human platelets express relatively high levels of ARAP1 compared to other tissues and ARAP1 is the only ARAP expressed in platelets. Indeed, we confirmed ARAP1 expression in human and mouse platelets, and show that ARAP1 is tyrosine phosphorylated upon platelet activation in a manner that is highly dependent on secondary signalling. At present the regulation and function of ARAP1 in platelets is completely unknown and this application therefore aims to obtain preliminary data using platelets that lack ARAP1 to demonstrate a role for ARAP1 in platelet function and thrombosis. This study will provide more insight in the underlying cause of platelet hyperactivity and potentially identify a novel target to prevent heart attacks and strokes. | null | HRCS2018_12286 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | IDENTIFICATION OF A NOVEL ANGIOPOIETIN 2 SIGNALLING CENTRE IN THE EMBRYONIC HAEMATOPOIETIC STEM CELL NICHE | Transplantations of haematopoietic stem cells (HSC) have been used in the clinic for several decades to treat various blood disorders. However, a significant shortage of donors for some patient groups means there is urgent need to find alternative sources of HSCs. A key goal of current haematology is the search for methods to efficiently produce HSCs in the laboratory. Pluripotent stem cells hold great hope for regenerative medicine, but generating HSCs from them remains a significant challenge, mainly since our current understanding of the mechanisms driving HSC development, particularly in human, is still extremely limited. Understanding how HSCs form in the embryo will be crucial in defining efficient protocols to generate HSCs in vitro. Our recent global transcriptome analysis revealed a novel signaling centre, Ang2, in the mouse aorta-gonad-mesonephros (AGM) region which we found is a strong stimulator of HSC development. We also observed a similar expression pattern in the human AGM region, suggestive of a previously undescribed important HSC regulatory centre. We propose a detailed investigation into the role of Ang2 signaling in human and mouse HSC development, using a combination of cutting-edge techniques including gene expression profiling of sorted cells, confocal immunophenotyping and loss/gain-of-function experiments followed by functional assays. To explore potential links with intra-aortic clusters in which HSCs form, we will use novel image-based spatial correlation analysis to create the first 3D models of the Ang2 signalling centre in the mouse and human AGM region. These and associated datasets will be a valuable resource for the research field to inform further functional studies. We will test whether Angpt2 can enhance haematopoietic differentiation of mouse and human ES cells. In the long term this could help development of a protocol for generating bone fide HSCs from pluripotent cell sources to meet clinical demands. | null | HRCS2018_12357 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Non-invasive assessment and management of coronary heart disease - a translational, data driven approach | The aim of the proposed research is to test and improve computational FFR software which can, using non-invasive patient measurements, determine the severity of a coronary artery stenosis. The improvements to the software would include the introduction of more automated, or semi-automated processes. By the end of the project, non-computational fluid dynamic specialists (possibly clinicians) would be able to use the software. Furthermore, machine learning will be performed on a data set of approximately 500 patients. The software, which has been developed in Swansea University, involves the segmentation of patient CT scans, after which reduced-order computational fluid dynamics is performed; this can be used to determine the pressure drop (FFR value) caused by the stenosis in the coronary arteries; and will be compared with the clinically measured FFR value for the patient to test the diagnostic accuracy of the software. Anonymised patient data, which includes CT scans and basic patient information (pressures, body mass index), can be collected through an existing agreement with Derriford hospital in Plymouth. Approximately 500 data sets will be collected for the project. Machine learning will be applied to the data set to determine if any underlying patterns can be found, which could lead to improved calculation of a patient's FFR value. In addition to valuable patient data, the opportunities of such a software could be widespread. The software could improve the patient treatment planning pathway. The methodology used only requires non-invasive patient measurements and imaging techniques. This could potentially reduce the cost of patient diagnosis; it would also improve patient experience, by avoiding invasive catheterisation procedures, and hence would not require patient recovery time. There is also a significant commercial opportunity of such a software. | null | HRCS2018_12590 | 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES | BLOOD |
Medical Research Council | MRC | A protein-transcriptome atlas of haematopoiesis across the human life span | The recent development of Cite-Seq technology coupled with the commercialization of dedicated antibody and droplet-based sequencing reagents represent a golden opportunity to generate a comprehensive Cite-Seq dataset to complement ongoing projects across the Human Cell Atlas Initiative. We have assembled a team of PIs with expert knowledge of human fetal and adult haematopoiesis as well as single cell molecular profiling techniques, complemented with expert collaborators with specialist knowledge of experimental and computational aspects of Cite-Seq technology. Cite-Seq technology enables the joint profiling of mRNA and protein from the same single cells using high-throughput next generation sequencing technology. The specific aims of our proposal are to (i) use Cite-Seq to generate combined protein and transcriptome profiles for over 550,000 haematopoietic progenitor and mature cells across the human lifespan, and (ii) to integrate the resulting datasets into the Human Cell Atlas data platform and establish pipelines for single cell multi-omics analysis. Subfractionation based on CD34+ and CD34- cell subsets will provide the progenitor and mature populations respectively. Samples will be obtained from fetal liver, yolk sac, and bone marrow, newborn cord blood, adult bone marrow and spleen and aged adult bone marrow. Sample acquisition will occur under already existing ethics permissions, thus ensuring that the project can start without any delay. The proposed Cite-Seq datasets for haematopoietic progenitor and mature cells across the human lifespan will provide a multiomic resource highly complementary to currently ongoing HCA projects. Development of data analysis and data integration pipelines will furthermore provide important guidance for future adaptation of the Cite-Seq method not just to projects mapping other tissues, but also to investigators studying blood and/or immune cell disorders. | null | HRCS2018_12652 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Department of Health and Social Care | NIHR | Transitions from paediatric to adult services for sickle cell disease (SCD): a prospective qualitative study examining young adult patients’ experiences | Transitions from paediatric to adult services cause problems worldwide, particularly among patients with chronic disease and complex health needs requiring integrated care. Transitional care is a key area within the NHS and sickle Cell Disease (SCD) provides an excellent case study for examining transitions. SCD is complex and growing rapidly in the UK, and there is little UK-based research on this topic. In the UK, over 15,000 people live with SCD, 2/3 of them in London. It is the fastest-growing genetic blood disorder in England with increasing associated mortality and morbidity: between 2001/2 – 2009/10, SCD-related hospital admissions increased more than 50%. The highest rates of emergency admissions were among those who recently transitioned from paediatric to adult care, suggesting an urgent need for improvement in transitional care. Yet we lack empirical evidence about the support patients need during such transitions. Transition is a time of increased medical vulnerability and morbidity, and increased responsibility for self-care. Despite the importance of effective transitioning for managing SCD, many young adults reach the transition period without appropriate support. This can have major negative consequences for them and for the health services, including missed appointments, poor treatment compliance and increased rates of emergency hospitalisations, sometimes with life threatening consequences. For patients with SCD, prevention and recognition of complications are crucial to maintain health. Poorly-managed transitions have high economic and social costs to patients, their families and health services. In this qualitative study, we examine the experiences of SCD patients aged 13-21 as they transition from paediatric to adult NHS services. The aim is to examine how transitions can be improved, with a strong focus on exploring patients’ own experiences of the healthcare services they receive and taking into account their broader social context, such as education, and relationships (e.g. family, friends). Research questions: (Q1) What support and information resources are required by patients to improve transitional care? (Q2) What do patients perceive as the ideal process of healthcare transition? (Q3) How does healthcare transition affect young adults’ healthcare-related behaviour (e.g. self-management) and quality of life over time? (Q4) How can patients’ personal histories (past SCD crises and general health) enable or hinder transition success? (Q5) How does social context (e.g. carer relationships) affect transition success (Q6) How can lessons from SCD be applied to other transitions? We will collect and analyse data from patient interviews, patient audio diaries, case notes and provider interviews. Outputs from this research will include (but are not limited to): SCD transitional care support and information resources co-produced with patients; SCD transitional care digital story co-produced with patients to raise awareness about the findings; recommendations for provider training and support for improving transitions; analysis of how our findings can apply to other related chronic conditions (SCD comorbid factors or which share its symptoms and care needs) by identifying generic aspects of transition e.g. how patients’ social contexts might shape their ability to move successfully into adult care. | null | HRCS2018_13706 | 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES | BLOOD |
Department of Health and Social Care | NIHR | Multicentre, open label, prospective, single arm study of the safety and impact of Eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome | Research Question: In patients on Eculizuamb treatment for aHUS (P) does withdrawal of treatment with monitoring (I) lead to equivalent rates adverse event compared to patients who remain on treatment (C)? If so this would change the way Eculizumab is used for the treatment of aHUS (O). Design: Single arm, open label study Setting: Secondary Care Population: Patients with a diagnosis of aHUS (www.rarerenal.org) receiving Eculizumab to treat disease in native or transplanted kidneys. Inclusion criteria: On Eculizumab treatment for at least 6 months, in remission with no evidence of ongoing disease activity and stable renal function with normal function or CKD stage 1-3. Exclusion criteria: Severe non-renal disease manifestations, loss of a previous transplant kidney to recurrent aHUS, pregnancy, unable to comply with monitoring protocol, pathogenic mutation in a transplant recipient. Health Technology: Withdrawal of Eculizumab replacing treatment with a system of medical and self-monitoring and treatment re-introduction if required. Measurement of Outcomes: The primary outcome is the number of withdrawal attributable adverse events during a two-year follow-up period. These events will be monitored continuously using the Bayes factor single arm design of Johnson and Cook. The trial will be stopped if the posterior probability that the primary outcome rate is equal to or higher than a pre-specified threshold (2 fold observed rate in patients on treatment). 6% of patients on Eculizumab experience a treatment related adverse event (observed in patients on treatment in the UK). The cost per successful withdrawal of Eculizumab and the incremental cost per quality adjusted life year over the 2 year follow-up period and patient life time will be estimated. The qualitative component of the study will provide an understanding of the factors that influence the decision of a patient (or carer) to withdraw from Eculizumab. Sample size: 30 patients. More than 100 patients will be on treatment in England during the study period and we will also recruit from devolved nations. Most will be eligible and we predict >30% of those eligible will agree to participate in the withdrawal study (based on PPI insights). An additional 20 patients who agree to participate in the qualitative and economic assessments (but not to withdraw from Eculizumab) will also be recruited. These patients will act as a comparator for the qualitative and health economic strands. Project timetable: Ethical, HRA and MHRA approvals, month -3-6; Site set up, month 6-12; Recruitment, month 6-21; Follow up, health economic and qualitative data collection, month 6-45; Data analysis, month 6-48; final analysis and write up, month 45-48. Team Expertise: The team includes clinicians with experience in the treatment of aHUS and conducting clinical trials in this disease. Co-applicants have expertise in trial design and analysis, qualitative research and health economics. Patients and the patient group have been involved in trial design and dissemination of information about the trial and collection of patient feedback. | null | HRCS2018_13863 | 6.1 PHARMACEUTICALS | BLOOD |
Department of Health and Social Care | NIHR | Patiromer for treating hyperkalaemia [ID877] | To appraise the clinical and cost effectiveness of patiromer within its marketing authorisation for treating hyperkalaemia. | null | HRCS2018_14193 | 6.1 PHARMACEUTICALS | BLOOD |
Health Education England | NIHR | Haemarthrosis of the ankle in haemophilia A and B: prevalence, impact and intervention | Haemophilia impairs bleeding control because of an absence of clotting factor VIII (haemophilia A) or factor IX (haemophilia B)1 resulting in bleeding into muscles and joints2. Although treatment with artificial clotting factor has some effect on frequency of bleeds, most patients still experience ongoing spontaneous and traumatic bleeds in joints3. Prolonged exposure of joint structures to blood leads to cartilage, structural and functional damage, ultimately resulting in pain and disability2,3. Damage also leads to changes in joint function furthering the risk of subsequent mechanical joint and soft tissue haemorrhage. Ultimately, this vicious cycle results in cumulative and irreversible damage to joints with severe reduction in mobility4. Prevalence of these accumulative episodes of bleeding has yet to been evaluated in detail. The tibiotalar (ankle) joint is the most commonly affected joint in the lower limb, accounting for one in five haemophilia-related bleeds in the United Kingdom5,6. Functional changes in the joint lead to a reduction in ankle range of motion (ROM) in patients over 30 years of age by as much as 80%3.Treatment with artificial clotting factor at the Leeds Comprehensive Care Centre (CCC) costs up to 7800 per bleed incident (70kg male) in addition to standard prophylaxis costs. A review of eight adult cases at Leeds CCC conducted in preparation for this application found a reduction in incidence of lower limb bleeds over 12 months from a mean at baseline of 11.6 bleeds/year to only 2.4 bleeds/year over the subsequent 12 month period wearing a prototype Leeds Ankle Stable Enhanced Rocker (LASER) boot and foot orthoses. Manchester foot pain and disability scores also indicated an 18.5% improvement in patient reported pain and disability scores. The use of foot orthoses and footwear modifications in haemophilia has not been investigated thoroughly. In other diseases such as rheumatoid arthritis, there is good evidence that orthoses prevent foot deformity and provide stabilisation7. As yet however, there have been no rigorous studies to address potential benefits of footwear and foot orthoses in blood-induced haemophilic arthropathy8. In patients with limited ROM, rocker profile shoe's supplement the rocker function of the ankle allowing forward progression and reducing the potential anatomical stress that may occur at the ankle joint. Rocker profile shoes have been used in conditions such as neuropathy to reduce foot pressures at anatomical sites of high pressure9. In haemarthrosis ,a rocker profile shoe has the potential to compensate for the reduction in ankle ROM9. Hypothesis: Foot orthoses and footwear modification can reduce the impact of ankle haemarthrosis by controlling joint function and thereby reducing the frequency of ankle bleeds in haemophilia. Aims To estimate the prevalence and impact of chronic haemarthrosis of the ankle joint. To investigate the mechanism of action of the Leeds Ankle Stabilising Enhanced Rocker (LASER) boot on ankle function. To evaluate the feasibility of conducting a randomised controlled trial (RCT) in the management of ankle haemarthrosis to evaluate clinical and cost effectiveness of treatment. Methods Prevalence study using a national haemophilia database and an associated multicentre questionnaire to explore the impact of ankle haemarthrosis in people with haemophilia. Mechanism of action study exploring the properties of the novel LASER boot and foot orthoses. A study to establish the feasibility of conducting an effectiveness RCT. Potential Benefits- Improved pain, disability and function in patients with haemophilia. - Prolonged ankle joint health, and reduced mechanical burden on the joint. - Reduced NHS costs by reducing ankle bleeds, and subsequent extra factor and on-demand treatment. - Delayed need for resultant ankle joint surgery. - Improved efficiency of national CCCs and regional haemophilia treatment centres (HCs). | null | HRCS2018_14639 | 6.3 MEDICAL DEVICES;2.4 SURVEILLANCE AND DISTRIBUTION | BLOOD |
Department of Health and Social Care | NIHR | To produce a cost effective immunoadsorption plasma filter for the production of blood group universal fresh frozen plasma and cryoprecipitate for transfusion. | Currently, plasma transfusion requires the donor and recipient to be blood group compatible. Plasma from donors of blood group AB is regarded as suitable for transfusion to any patient, because it does not contain anti-A or anti-B: if present these antibodies can bind to a patient's red blood cells causing haemolysis and even death. Only 4% of the UK population are group AB, and there is currently no alternative UP available in the UK, so group A plasma which has low levels of anti-B antibodies has been recommended as an alternative for when a patient s blood group is unknown. However, this practice is undesirable because: - there is a potential risk of haemolytic transfusion reactions developing in group B or AB individuals, especially when large volumes of plasma are transfused; - the wrong plasma group could be transfused to patients as a result of human error, particularly in emergency situations (these are considered never events in the NHS); - it delays the provision of plasma in bleeding situations, which could be detrimental to a patient s outcome; - it causes significant wastage of a precious resource in the NHS; - during mass casualty incidents it is difficult to meet the demand for AB and A plasma for NHS hospitals without compromising the supply of other blood components which are as important in these situations for treating injured patients. As the demand for plasma has increased over the last decade, and with the number of major incidents rising in the UK, there is a need for NHSBT to address these issues through developing a universal plasma. It is possible to remove anti-A and anti-B from plasma by filtration, and this project aims to develop a filter that could be applied to plasma of any blood group to render it universal (i.e. by removal of anti-A and anti-B). A team of transfusion laboratory and clinical medicine experts, together with commercial partners have shown in proof of principle studies that this is feasible and that the activity of processed-plasma is maintained. The objective of this project is to build upon this work by: a) scaling up production of the filter to support the manufacture of large-volumes of universal plasma suitable for routine use by global blood services, and b) complete pre-clinical evaluations ready for subsequent CE marking and development by industry. In addition to developing the filter, we will also consult with regulators, clinicians and patients to ensure that the performance of the filter meets their requirements and that it is safe and effective. We will transfer the technology and perform pre-clinical testing to a stage where it becomes commercially viable for a manufacturer to take forward to market. Key deliverables will be to demonstrate that: (i) a cost-effective manufacturing method to produce filters has been developed; (ii) the manufactured filters meet the design specification for plasma quality; (iii) the manufactured filters meet the required specification to remove target antibodies; (iv) the raw materials used are safe; (v) all required preclinical testing data is generated to support an application for CE marking/further clinical trials; (vi) the filter has been developed in accordance with ISO 13485:2016, (vii) a further survey is produced to assess the international market potential and barriers to adoption. | null | HRCS2018_14807 | 5.4 SURGERY | BLOOD |
Department of Health and Social Care | NIHR | Lusutrombopag and avatrombopag for Thrombocytopenia (severe, chronic liver disease, surgery) [ID1520] | To systematically review the effectiveness and estimate the cost effectiveness of avatrombopag versus lusutrombopag versus established clinical management without avatrombopag and lusutrombopag (including, but not limited to platelet transfusion) for people with thrombocytopenia associated with chronic liver disease needing an elective procedure. | null | HRCS2018_15839 | 6.1 PHARMACEUTICALS | BLOOD |
Department of Health and Social Care | NIHR | Development Of a haemophiLia PHysiotherapy INtervention for optimum musculoskeletal health (DOLPHIN) - feasibility of a randomised controlled trial | Background: Haemophilia is a rare inherited disorder affecting 1:10,000 of the population, in which the blood does not clot normally, leading to repeated bleeding into joints (haemarthroses) and muscles (haematomas).1 Recurrent haemarthroses trigger a degenerative irreversible process of synovial hypertrophy, articular cartilage and chondral bone erosion. As a result of bleeding during childhood, joints and muscles become painful, swollen and difficult to move (haemophilic arthropathy).2 Health-related quality of life and academic achievement are reduced and are closely associated with the number of bleeding episodes.3-4 Prevention of arthropathy is the major goal of haemophilia treatment and regular prophylactic treatment with missing coagulation factors at an estimated cost per child of £60,000 per annum, has significantly reduced, but not alleviated all joint bleeding. Evidence indicates that children still bleed 1-2 times per year, and the potential for disabling arthropathy remains.5-6 Exercise to increase muscle strength is recommended to improve joint health but there is a lack of robust evidence that this has a significant effect on progression of synovitis and haemophilic arthropathy, or the children's participation in physical activities. Aims and research question: Our aim is to develop a muscle strengthening exercise intervention with potential to improve musculoskeletal health and determine if it is feasible to conduct a clinical trial to test its effectiveness in comparison to usual physiotherapy practice on musculoskeletal health and the progression of haemophilic arthropathy in children with haemophilia. We will carry out a feasibility study to assess key features of study design and project management, including; recruitment and retention rate, willingness of participants to be randomised, exercise adherence, safety and training needs, appropriateness of the outcome measures and explore factors that influence acceptability of the trial and intervention. Plan of investigation: In 3 interlinked studies we will; Develop a muscle strengthening intervention aimed at improving musculoskeletal health and reducing progression of haemophilic arthropathy by systematically reviewing current evidence, consulting clinicians experienced in haemophilia care and children with haemophilia and their families. Conduct a feasibility trial at two UK Haemophilia Centres of the muscle strengthening exercise intervention to usual physiotherapy care. Determine the relevant costs associated with this study in order to carry out an economic evaluation of the exercise intervention. Benefits to patients and the NHS: Disabling physical limitation and pain are the main co-morbidity of haemophilia. One of the important issues for children with haemophilia is participating in games and activities with their friends and for parents of the children it is being able to make informed decisions regarding their child's condition. This research will allow us to design a robust clinical trial of a low cost age-appropriate intervention that enhances musculoskeletal health and minimises bleeding episodes enabling safe participation in games and activities and in the long term improve their well being, quality of life and lessen disability later in life. Information about whether muscle strengthening exercise is safe and beneficial for optimum musculoskeletal health will enable parents to make informed decisions about their child's condition. With treatment costs exceeding £60,000 per year per child and an almost three-fold increase in overall healthcare costs in those with signs of joint arthropathy, by enhancing musculoskeletal health we expect to reduce the individual, medical and societal cost and burden of haemophilia. | null | HRCS2018_15932 | 6.7 PHYSICAL | BLOOD |
Department of Health and Social Care | NIHR | Halting olfactory haemorrhage with Tranexamic acid in the Emergency Room | Background: Far from being trivial, epistaxis (nosebleed) can be fatal with over 60,000 UK Emergency Department (ED) attendances per year, resulting in over 20,000 emergency hospital admissions (>40,000 hospital bed days) each year. In one third of cases presenting to the ED, bleeding fails to settle with the simple measures described and patients undergo painful anterior nasal packing to control the haemorrhage5. This involves insertion of a firm nasal tampon measuring approximately 10-15 centimetres, which is painful for patients and has a 28% incidence of complications6. Tranexamic acid (TXA) is an inexpensive, safe treatment that prevents blood clot breakdown. Given intravenously, it reduces mortality following surgery and major trauma7. Applied topically after surgery, TXA reduces blood loss and the need for blood transfusion8. In epistaxis, a small trial with important methodological limitations suggested that topical TXA may reduce bleeding while improving patient satisfaction9. A well-designed randomised controlled trial is now urgently warranted to evaluate whether this simple treatment can reduce the need for anterior nasal packing and hospital admission. Aims: the aim of the study is to establish whether topical intranasal TXA may be used as an adjunct to standard therapy in patients presenting to the Emergency Department with spontaneous atraumatic epistaxis to reduce the need for anterior nasal packing compared to placebo. Secondary outcomes of the study are to assess the impact of the use of topical TXA on the need for hospital admission, the subsequent length of stay, need for blood products and the re-bleeding rate for patients subsequently discharged home. We will also monitor thrombotic complications as this is a potential side effect of TXA although this is considered a negligible risk with the low dose topical TXA used in this study. Research Question: in adult patients with acute spontaneous epistaxis does topical intranasal TXA used in addition to standard therapy reduce the need for intranasal packing? Plan of investigation: we plan to conduct a multi-centre randomised controlled trial comparing the use of TXA soaked on a cotton wool dental roll and inserted up the bleeding nostril to placebo. Adult patients presenting to the ED with epistaxis that persists after simple first aid, followed by 10 minutes of topical application of a vasoconstrictor (phenylephedrine) will be screened for eligibility. Eligible and consenting patients will have a soft dental roll soaked in 2mls of either TXA or placebo inserted into the external nasal orifice and held in place with gentle pinching of the nose for a further 10 minutes before removal. Patients will be assessed 2 minutes after its removal for continued bleeding, with the primary outcome being the need for subsequent anterior nasal packing. Secondary outcomes will be hospital admission, rebleeding, need for subsequent blood transfusion and thrombotic complications within 7 days. Potential benefits to patients and the NHS: Epistaxis represents a frequent ED presentation associated with significant morbidity and even mortality. Packing, whilst an effective method for controlling bleeding, is poorly tolerated, distressing and associated with significant complications. Application of topical intranasal TXA is an inexpensive procedure which, if effective, has the potential to provide better control of epistaxis, reduction in the need for packing and hence hospital admission. Thus, it has potential to be of real benefit to patients while reducing NHS costs. | null | HRCS2018_15938 | 6.1 PHARMACEUTICALS | BLOOD |
Department of Health and Social Care | NIHR | A multicentre randomised trial of first line treatment pathways for newly diagnosed immune thrombocytopenia: Standard steroid treatment versus combined steroid and mycophenolate. | Immune thrombocytopenia (ITP) has an incidence of 2.9/100,000 person-years1. It is an autoimmune condition that presents with bleeding and bruising due to a low platelet count. There is increased consumption and reduced production of platelets due to both antibody and cell mediated autoimmune attack of platelets and megakaryocytes involving dysregulated autoreactive T and B cell lymphocytes2-13. Currently the standard care is initially to treat with high dose steroids and this has not been challenged for decades. Although 80% of patients respond, relapse rates are high when these steroids are reduced or stopped (70-90%) and steroid side effects are a major problem14,15. A published survey of ITP patients reported 98% had at least one side effect and 38% stopped or reduced dosage due to intolerable side effects16. Patients who relapse are at risk of bleeding, which occasionally can be severe including intracranial haemorrhage17. Fatigue is also associated with disease activity and can be severe18. Physical factors combine with psychological stress through fear of bleeding, need for time off work and lifestyle restrictions due to bleeding risk to adversely impact quality of life19,20. In the UK, mycophenolate (MMF) is becoming a popular second line agent due to its good side effect profile and efficacy, with response rates reported between 50- 80%21-27. However, as MMF has a slow onset of action (up to 2 months), patients may need bridging with further steroid. Mycophenolate has activity against both autoreactive T and B cells and has also shown efficacy in refractory ITP including steroid resistance suggesting a complimentary mechanism of action25. It is less expensive to the NHS than some other second line options costing approximately £182/year (generic cost) compared to costs for average doses of romiplostim at £25 000/year, Eltrombopag £20 000/year or rituximab at £8000 for a course of 4 infusions. We are proposing to bring forward the timing of MMF treatment from second to first line in the hope of preventing the almost inevitable first relapse. By giving patients a stable platelet count sooner we expect to improve other outcomes such as quality of life and fatigue. However, there will be some patients who will be treated with MMF who may have been successfully treated with steroids alone (10-30%). Similar to other immunosuppressives, MMF may slightly increase infection and cancer risk with long term use. This puts the trial in equipoise. The proposal includes a strategy to reduce and stop MMF at 6 months for patients in complete remission to prevent unnecessary long term use. This trial proposal has received support from clinicians and patients nationally (UK ITP forum and ITP support association). To ensure objective and meaningful outcomes, it will be a multicentre RCT recruiting 120 patients. Patients will be given up to one week of steroid prior to randomisation to enable sufficient time to read information, discuss and ask questions with informed consent in an appropriate setting. Patients will receive the usual follow up according to clinical need and local policy. Laboratory and clinical data will be collected from routine appointments. In addition, patient oriented outcomes will be recorded at diagnosis, 2, 4, 6, and 12 months using validated questionnaires for quality of life, fatigue and time off work. If the results challenge the current first line treatment, a change to the standard of care could be implemented within 5 years with potential to improve patients lives with a new diagnosis of ITP. Potential indirect benefits to the NHS include reduced need for hospital attendances and admissions. This will be the first UK multicentre ITP RCT and if successful represents a platform for future trials. | null | HRCS2018_16015 | 6.1 PHARMACEUTICALS | BLOOD |
Wellcome Trust | WT | A Device for the removal of circulating autophagic vesicles in patients with sickle cell disease | Sickle Cell Disease(SCD) is the commonest inherited genetic disorder in the UK with 14,000 patients and over 300 affected children born annually. There are three disease modifying treatments available, hydroxyurea, blood transfusion and stem cell transplant. Of these, transfusion is the mainstay of preventative treatment. However, there are frequent clinical situations where transfusion would be recommended but blood is not available in sufficient quantity on a regular basis or not available at all. Ninety percent of patients with SCD worldwide live in the developing world where there is no safe and freely available access to blood. Consequently, there is a need for a novel therapy that does not require donated red cells. Professor David Anstee proposes a novel technology to address this need. Recent work in his laboratory at NHS Blood and Transplant in Bristol has shown that a critical step in the formation of normal red blood cells involves the removal of membranous vesicles containing waste products from immature red cells when the cells pass through the spleen. Patients with SCD lose the function of their spleen very early in life and as a consequence vesicles cannot be removed and remain in their blood. The vesicles that are retained in the peripheral circulation likely contribute to the pathology of SCD. Professor Anstee and colleagues are developing a device to selectively remove these vesicles from the blood of patients with SCD and anticipate that patients undergoing this treatment will enjoy a dramatic improvement in their quality of life. | null | HRCS2018_20229 | 5.3 MEDICAL DEVICES | BLOOD |
Medical Research Council | MRC | Two tier protection and metabolic genotoxicity during blood production | We investigate how cells and organisms repair highly toxic DNA interstrand crosslinks. In the human inherited illness Fanconi’s anaemia the repair of DNA crosslinks fails, causing developmental defects, bone marrow failure, and marked cancer predisposition. Over the last 5 years our research has made important contributions in understanding how the FA genes promote crosslink repair; how the biochemical regulation of the FA repair pathway works; how the new genes identified function in this pathway; and the creation of mouse models which revealed that an in vivo role of the FA pathway working together with aldehyde dehydrogenases protects against endogenous genotoxic aldehydes (two-tier protection). In the future, our research plans will build on these foundations. We wish to define the molecular and genetic basis of the repair of DNA crosslinks caused by known mutagens and endogenous aldehydes. We want explain how aldehyde mediated DNA damage corrupts development and causes carcinogenesis. Finally, our discoveries have shown that the two-tier protection mechanism against endogenous aldehydes is crucial for stem cell maintenance. We want to better understand how this protection mechanism is regulated within stem cells, and the physiological consequences when it fails. | null | HRCS22_01250 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Haematopoietic stem cell fitness mechanisms | Multipotent self-renewing haematopoietic stem cells (HSCs) are essential for human health and the curative potential of HSC transplantation therapies. I joined the MRC Molecular Haematology Unit (MHU) in April 2021 to investigate mechanisms regulating HSC activity and to apply this knowledge to improve therapies for haematological diseases. The specific aim of my research programme is to define mechanisms regulating HSC fitness. High fitness HSCs display durable and balanced blood system reconstitution activity. By contrast, low fitness HSCs have weak or biased activity and are thought to contribute to various pathologies, particularly age-associated haematopoietic diseases and complications following HSC transplantation. However, our understanding of what determines HSC fitness is still incomplete. Additionally, despite increasing interest in the clinical applications of ex vivo cultured HSCs for cell and gene therapies, our knowledge of HSC fitness in the context of ex vivo expansion is still poorly developed. Within this programme, we plan to undertake: (1) A candidate-based approach to investigate epigenetic regulators of HSC fitness. We recently identified several epigenetic factors as novel regulators of HSC expansion potential and now aim to better understand how these novel epigenetic factors regulate HSC activity and fitness. With collaborators in the MHU, I will investigate the roles of these epigenetic regulators through molecular, cellular, and functional assays. These studies aim to improve our understanding of how HSC fitness is regulated at the epigenetic level. (2) A screening-based approach to identify novel mechanisms of HSC fitness. With HSC experts within the MHU, we will perform genetic and small molecule screening to identify key factors and pathways regulating HSC fitness and identify new strategies to improve ex vivo HSC expansion and manipulation. Together, this research programme aims to provide novel insights into HSC biology and to help develop next-generation HSC therapies. | null | HRCS22_01251 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | MICA: Hydroxyurea - Pragmatic Reduction In Mortality and Economic burden (H-PRIME) | H-PRIME will be a phase III 2x2x2 factorial randomised partially placebo-controlled trial. We aim to conduct a policy changing trial to address three key interventions that could make a substantial difference to the lives of children born with sickle cell anaemia (SCA) in low-income regions in sub-Saharan Africa. H-PRIME will answer all three questions efficiently in a single clinical trial. We will recruit 1800 children with confirmed SCA at three sites in Eastern Uganda who will be randomised to: (1) daily oral hydroxyurea vs placebo; (2) enhanced antimalarial prophylaxis with monthly dihydroartemisinin-piperaquine (DHA-PQP) vs standard of care (SOC) (monthly sulphadoxine-pyrimethamine, SP) (open-label) and (3) enhanced antimicrobial prophylaxis with daily co-trimoxazole (CTX) AND twice-daily penicillin V throughout childhood vs SOC (twice-daily penicillin V until the age of 5 years; open-label). A 3-month pre-treatment screening and observation period will allow diagnostic confirmation of SCA status and the collection of baseline data on clinical event rates, laboratory variables and potential confounders. The primary outcome the hydroxyurea randomization will be death from any cause. The primary outcome for the anti-malarial randomisation will be malaria-associated hospitalisation while for the antibiotic randomisation it will be hospital admission (all-cause, due to the challenges in diagnosing bacterial infections as above). Assuming recruitment over 2 years, a maximum 4 years of follow-up, 10% loss to follow-up at 4 years and mortality in the control arm of 2.6/100CY (i.e. 10% cumulative mortality at 4 years, H-PRIME will provide 90% power to detect a 50% relative reduction for hydroxyurea vs placebo. The study will provide 86% power to detect a 36% relative reduction from 4.7 to 3.0 malaria-associated hospitalisations/100CY respectively and 87% power to detect a 20% relative reduction from 20 to16 all-cause hospitalisations/100CY respectively. | null | HRCS22_01845 | 6.1 PHARMACEUTICALS | BLOOD |
Medical Research Council | MRC | Developing human model cellular systems for studying Red Blood Cell diseases and as screening platforms | Thalassemia syndromes and sickle cell disease (SCD) represent a significant global health problem and financial burden to health services. Studying these diseases is severely impeded by paucity of suitable and adequate quantities of material from patients, and lack of suitable cell lines. Mouse models of the diseases are therefore routinely used for biological studies and drug evaluation, but fundamental differences exist between mouse and human erythropoiesis. New approaches and human systems for these disorders are therefore essential. We have recently created 1) the first immortalised adult human erythroid cell line (BEL-A) that recapitulates normal erythropoiesis, expresses normal levels of adult globin, terminally differentiates and enucleates to generate mature reticulocytes, providing a sustainable supply of cells we have extensively characterised 2) a platform for CRISPR genome editing of BEL-A cells, creating sublines with single or multiple gene edits. We now have opportunity to exploit these tools and technologies to create lines as human model cellular systems of RBC diseases, providing a sustainable and reproducible supply of cells for study. Disease mutations will be introduced into BEL-A cells via CRISPR. We aim to create a range of beta and alpha thalassemia lines with mutations associated with different disease severity, and a SCD line. Such a compendium of lines for a disease will also help determine variability in disease mechanisms, as well as evaluation of drugs etc across spectra of phenotypes. Importantly all lines will have a constant genetic background, and the same as the founder line, negating the many experimental variables between patient samples Lines will undergo extensive characterisation using a wide range of approaches both to validate disease phenotype and to provide a data resource to facilitate application of the lines by ourselves and others, including comparative proteomics to also identify novel dysregulated proteins. | null | HRCS22_01999 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | Control of blood cell emergence by YAP and environmental cues | The haematopoietic system is maintained throughout adult life by haematopoietic stem cells that produce a constant supply of all blood cells. In the clinic, these stem cells are the cells which upon transplantation successfully restore the blood system in a range of disease. One major limitation to the use of blood stem cell transplantation in the clinic is the restricted availability of compatible donor for graft recipients. The possibility to generate these blood stem cells in vitro for clinical purposes would significantly advance the use of this curative treatment. Pluripotent stem cells can be efficiently differentiated in vitro to form all blood progenitors but researchers are still struggling to generate blood stem cells. Here we propose to investigate how the mechanotransducer YAP might regulate the emergence of blood cells from hemogenic endothelium during embryonic development. Through gain and loss of function, we will determine how changes in YAP activity impact the generation of blood progenitors upon the in vitro differentiation of embryonic stem cells. Additionally, we will determine whether cellular responses to change in environmental cues, such as adhesiveness, are controlled by YAP. Flow cytometry, time lapse imaging and clonogenic assays will be used to determine the outcome of the culture upon changes in the microenvironment and YAP activity level. This knowledge will allow us ultimately to more precisely control and manipulate biophysical properties for the design of artificial niches to generate blood stem cells usable in the clinic. | null | HRCS22_02141 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Switching mammalian genes on and off during development, lineage specification, and differentiation, and its impact on human genetic disease | This programme addresses a key question in biomedical research: how are genes switched on and off during development, lineage commitment, differentiation and maturation? To date we know that this involves the three fundamental regulatory elements of the genome: enhancers, promoters and boundary elements. Here we investigate how these elements interact to regulate gene expression in three-dimensional space and time. To address this, we study how the human and mouse alpha-globin multi-gene clusters are switched on and off as haematopoietic stem cells differentiate into mature erythroid cells. Past lessons from studying globin gene expression have elucidated many of the general principles underpinning our understanding of mammalian gene regulation. Using newly developed synthetic biology, and proteomics approaches, together with new experimental models, the unanswered questions we address here are: how do promoters and enhancers come into close physical contact; how do enhancers interact specifically with their cognate promoters; what specifically does the enhancer bring to the promoter and how does this alter the transcription cycle; what is the role of CTCF binding sites in this process? While elucidating the normal process of gene regulation we will also examine how this process is perturbed in human genetic diseases. Studying globin gene disorders has elucidated many general principles underlying human genetic disease. While some single gene disorders are known to result from mutations in promoters and enhancers, it seems likely that variations in gene expression underlying complex diseases and variable human traits mainly affect the regulatory landscape. Our programme will address in detail, how changes in intergenic DNA may influence gene expression. Finally, we are using this information to develop new approaches to regulating gene expression via genome editing in pre-clinical and eventually clinical studies by manipulating haematopoietic stem cells | null | HRCS22_02270 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Counteracting hematopoietic ageing by pharmacological inhibition of TGFbeta and IL-6 signaling | Ageing of the hematopoietic system is associated with declining erythropoiesis and lymphopoiesis, leading to decreased adaptive immunity and frequent anemia, together contributing to multiple age-related morbidities, including cognitive decline, decreased muscle strength, cardiovascular problems and susceptibility to infection. Using an unbiased approach to the identification of changes to the aged bone marrow microenvironment we identified the IL-6 and TGFbeta signalling pathways as up-regulated. We found that TGFbeta signaling plays a key role in sustaining increased HSC platelet priming in aged mice, as pharmacological inhibition of TGFbetaR1 lead to decreased HSC numbers and strong depletion of HSC platelet priming. Importantly, this was accompanied both by increased lymphoid priming of MPPs and rebalancing of HSC output in competitive repopulation assays, indicating that TGFbetaR1 inhibition provides a means to improve lymphopoiesis in aged hematopoiesis. In the present proposal we will measure the stability of the rebalancing of HSC lineage output after TGFbetaR1 inhibitor withdrawal, as well as the ability of TGFbetaR1 inhibition to improve the output of naïve, antigen-responsive lymphocytes. In addition, we observed that both IL-6 and TGFbeta signalling contributed to the age-dependent decrease in erythropoiesis: inhibition of IL-6 using a neutralising antibody reversed the age-dependent decline in erythroid progenitor function, whereas TGFbetaR1 inhibition improved erythroid progenitor output. We will therefore now test the ability of combined IL-6 and TGFbetaR1 inhibition to improve erythropoiesis, and in particular to restore peripheral blood hemoglobin levels, as this is the key parameter correlated to age-related multimorbidity. These studies will determine if TGFbetaR1 and IL-6 inhibition has therapeutic potential in aged hematopoiesis, and since drugs targeting these pathways are available, the potential for clinical application. | null | HRCS22_02274 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | The role of the endothelium in traumatic coagulopathy. | As a clinician specialising in bleeding disorders, and as the Chair of the Major Haemorrhage Committee, I have seen how important it is to develop effective treatments for trauma-related-haemorrhage. Mortality associated with major bleeding is high and the lack of understanding of how coagulopathy develops in patients with uncontrolled bleeding underpins the lack of effective treatments. Aim: to understand the pathophysiology of acute traumatic coagulopathy, with a focus on the endothelial/coagulation interface. Objective 1: To critically evaluate the effects of thrombomodulin (TM) in vitro on key clotting factors in trauma coagulopathy using two dynamic haemostasis assays. Objective 2: To develop an endothelial model of trauma coagulopathy using blood outgrowth endothelial cells (BOECs). Objective 3: To investigate the effects of thrombomodulin on thrombus formation using the BOEC trauma model under flow conditions. I will set up a study to collect blood and plasma samples from 20 healthy volunteers and from 2 members of a family with a known THBD variant. I set up the ACIT-2 study in Oxford in 2010 and with my ongoing oversight it continues to recruit patients. Detailed clinical data and linked plasma samples have been collected according to the REC approved study protocol. All studies will comply and follow the Codes of Practice issued by the Human Tissue Authority. The dynamic real time haemostasis assays, and the ELISA tests will be conducted at the Oxford Haemophilia and Thrombosis Centre using existing resources. The BOEC work, in both static and flow conditions, will be completed within Professor Choudhury's laboratory within the Division of Cardiovascular Medicine, Oxford University using existing resources. Outcomes: My goal is to develop a robust 'trauma endothelial' model which will form the basis for future work exploring the key endothelial drivers of trauma coagulopathy and which will lead on to the testing of potential therapeutic targets. | null | HRCS22_02355 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | Improving cardiovascular outcomes in polycythaemia by risk stratification and targeted therapy. | Thrombosis remains the major cause of morbidity and early mortality in JAK2 positive polycythaemia (PV). Preventative strategies are based on two RCTs which showed benefit of low-dose aspirin and venesection to maintain haematocrit <0.45. Patients considered at higher thrombosis risk are given additional cytoreductive therapy (hydroxyurea or interferon) with recognised side-effects, and with limited evidence of benefit for thrombotic risk. This collaboration brings together a national clinical expert in thrombosis, with a strong interest and background in laboratory haemostasis research, with internationally recognised scientific and clinical leaders in PV. A sub-study will be added to a large RCT of ruxolitinib against standard cytoreduction for treatment of high risk PV to prospectively measure state of the art biomarkers of platelet, endothelial and coagulation activation (baseline and after 6 months of treatment). The pattern of biomarkers will be analysed and correlated with clinical events. Additional work will be undertaken on a smaller number of samples (both before and after treatment) to study the mechanisms of thrombotic risk; testing the hypothesis of the central role of NETosis, triggered by activated platelets, in driving thrombosis. Planned techniques: ELISAs for biomarkers, flow cytometry for markers of platelet and neutrophil activation and platelet-neutrophil interactions; NETosis to various stimuli by MPO/DNA ELISA, and by immunofluorescence and microscopy techniques. This proposal will establish a set of biomarkers to improve thrombotic risk stratification, and improve mechanistic understanding, leading to personalised, targeted therapy to reduce thrombosis risk in PV. It will also be highly relevant for other conditions in which NETs have been implicated in thrombosis, including cancer and inflammatory/autoimmune conditions. | null | HRCS22_02358 | 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES | BLOOD |
Medical Research Council | MRC | Optimisation of the manufacture of a homogeneous synthetic haemoglobin as a novel Oxygen Therapeutic / Blood Substitute | There is significant clinical need for a synthetic oxygen therapeutic / blood substitute that is both long-lasting and sterile. As haemoglobin (Hb) is the body's natural oxygen carrier the use of cell-free Hb is an ideal starting material for such an agent. However, such Haemoglobin-Based Oxygen Carriers (HBOCs) display an inherent capacity to induce cytotoxicity through oxidative reactions, causing cell and tissue damage. They also scavenge nitric oxide (NO) leading to hypertensive effects. Through previous MRC funding, we successfully developed an engineered HBOC that overcome the limitations and toxicities of previous generations. The addition of our patented, genetically engineered 'through protein electron pathways' enhances the capacity of plasma reductants to prevent cytotoxic oxidative reactions. In addition, mutations that decrease NO scavenging have been added, avoiding the heme loss and complement activation that has compromised a previous recombinantly produced HBOC with this property. The focused aim of this current project is to use the expertise developed in our previous MRC DPFS-funded success by developing a manufacturing pathway to clinical trials for our product. Meeting the exacting GMP standards required by regulators is essential. Working with a technology and innovation centre (CPI) we will develop a scalable GMP-compliant manufacturing process. We will utilise our novel engineered system of PEGylation (patent filed) that overcomes the issue of heterogenous PEGylation seen with previous methodologies. This has the added unique benefit of not interfering with O2 binding or cooperativity. Finally, we will show that the previous issues with HBOCS have been addressed through demonstration of product quality, safety and efficacy in animal models, that will help attract future funding for a full program of preclinical and clinical trials. | null | HRCS22_02379 | 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS | BLOOD |
Medical Research Council | MRC | Generating platelets in vitro for the clinic: optimisation and added clinical efficacy | The project is divided in 4 workpackages WP1. Identification of efficient hPSC lines. Ghevaert and Eto have tested between them 55 iPSC lines to identify good/bad MK producers. We will carry out whole genome expression and epigegetic study to pinpoint markers that identify good cell lines to facilitate the choice of clinical grade starting material. WP2. Identification of MKProgs identity and optimisation of culture The culture method used by both Ghevaert and Eto rely on the generation of MK progenitors. To maximise their formation and subsequently maintain their expansion in culture we will: a. Identify markers to be able to quantify MK progenitor formation and culture monitoring using single cell sequencing./phenotyping b. Understand the pathway of differentiation though dynamic analysis of the culture using single cell sequencing c. Look at transcription regulatory networks during differentiation and what drives cell fate lineage d. Use knowledge developed in a. to c. in order to optimise two key step of the culture: formation of MKProgs in the early stage and MKProgs maintenance without exhaustion in the expansion phase. WP3. We will test soluble small molecules that promote platelet formation in platelet donors in the bioreactor developed by Eto (VerMES) to increase platelet formation in vitro and subsequently test the functionality of the platelets released in the presence of these small molecules. WP4. We will supercharged platelets by targeting chosen proteins to the alpha granules using an expression vector already in use by Ghevaert. We will overexpress FVIIa, BMP-2/-4 and LL-34/-37 and test the supercharged platelets for increased haemostasis, bone repair and control of staphylococcal infection respectively. | null | HRCS22_02599 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | Human blood stem cell expansion: Empowering new technology for stem cell medicine | Despite significant efforts and investment, researchers have largely failed to maintain fully functional HSCs for substantial periods of time. The current state-of-the-art in therapeutic applications is to therefore minimise the amount of time that HSCs are kept outside the body, imposing a number of limitations on clinical protocols. Recent advances in mouse HSC expansion (Wilkinson/Ishida et al., Nature 2019) put us on the cusp of breaking through this decades-old barrier and this novel cell culture system urgently requires molecular characterisation and translation to human HSCs. Concomitant advances in single cell gene expression and proteomics technologies permits us to assess the molecular circuitry of cell systems at unprecedented resolution. Our proposal brings together leading UK and Japanese researchers in the molecular and functional characterisation of mouse and human HSCs in order to leverage their complementary expertise to translate this technology to the human system: The proposal has two broad aims: 1) Molecular characterisation of pathways that maximally support mouse blood stem cell expansion 2) Utilisation of human HSC expansion conditions to study HSC biology and examine potential clinical applications We have assembled a collaborative research team with expertise in the cellular (Japan) and molecular (UK) characterisation of both mouse and human blood stem cells. DK has a long track record in the molecular characterisation of both normal and malignant blood cell populations and SY has pioneered the amplification of large numbers of normal haematopoietic stem cells in mice. The project will be further enhanced by one UK and one Japanese co-investigator, with BG's longstanding expertise in the analysis of single cell and bulk transcriptional datasets helping with the computational analysis of datasets and YT's efforts to expand leukaemia stem cells directly addressing one potential clinical benefit of this project. | null | HRCS22_02602 | 5.2 CELLULAR AND GENE THERAPIES | BLOOD |
Medical Research Council | MRC | UNDERSTANDING MOLECULAR MECHANISMS UNDERLYING DEVELOPMENT OF HIGHLY REGENERATIVE HUMAN HAEMATOPOIETIC STEM CELLS | Over 50,000 HSC transplantations in clinics are performed annually worldwide, but demand outstrips supply. Despite widespread efforts, the search for methods enabling the generation of bona fide HSCs in vitro has met with limited success, primarily due to poor understanding of molecular mechanisms underlying HSC development in the embryo, particularly in humans. We have shown that the first HSCs emerging in the human embryo possess enormous regenerative potential, significantly exceeding that of HSCs from adult sources, making their properties highly attractive for clinical applications. It is therefore important to elucidate the genetic mechanisms underpinning emergence of these HSCs. This is the main focus of our research project. Our recent analysis identified the genes that are expressed in these HSCs, but are silent in their counterparts derived from human pluripotent stem cells (hPSCs). Some of these genes must be responsible for the development of highly regenerative HSCs in the embryo. We have also identified hPSC-specific genes, which might be negative regulators of HSC development. Based on our unique expertise in functional analysis of human embryo HSC development, we will interrogate gene functions using efficient in vitro and in vivo screening systems with the focus on transcription factors (TFs) that are key cell fate regulators. To delineate key molecular mechanisms underlying HSC development, we will explore a spectrum of biological effects elicited by TFs and ultimately determine their capacity to transform hPSCs-derived progenitors into transplantable HSCs. This study will provide deep mechanistic insight into normal and potentially congenital pathological processes underlying human blood development and inform strategies to gain better control of ex vivo HSC manipulations. Ultimately, this is critical to drive forward new cell-based therapies to meet clinical demand for HSCs and help move medical treatment towards personalized medicine | null | HRCS22_02734 | 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING | BLOOD |
Medical Research Council | MRC | A molecular and structural approach to understanding interstrand crosslink incision by the Fanconi anaemia DNA repair pathway | Loss of genomic stability elicits disease and is a trigger for human ageing. During every cell division, structural aberrations in the DNA can block the progression of DNA replication. The inherited syndrome Fanconi anaemia (FA) produces devastating and often lethal clinical features including bone marrow failure, developmental defects and solid and haematological malignancies. The cellular defect in FA is an inability to purge the genome of DNA interstrand crosslinks (ICLs), using the 'FA' DNA repair pathway. ICLs are amongst the most toxic forms of DNA damage known and arise when duplex DNA strands become covalently linked. Despite advances in identifying key components and landmark steps, key molecular details of how the FA pathway co-ordinate to ICL processing removal are obscure. Here, we will bring together a powerful combination of nucleic acid chemistry, protein biochemistry with structural and molecular biology to reveal the mechanistic details of FA pathway operation. We will focus on the pivotal step of ICL incision by the DNA cutting enzyme XPF-ERCC1 and how the localisation of this complex is regulated by additional key FA proteins including FAND2 and FANCI. Our approach will allow us to iteratively test the functional importance of the structural features identified using biochemical DNA repair reactions. By studying this repair pathway in unprecedented detail and depth, we will transform our understanding of the FA and open-up new avenues to treat affected patients. The genes defective in FA are also associated with predisposition to disease in the population more generally and represent attractive therapeutic targets, including in cancer treatment. Our work will, therefore, be vital to enable the targeting FA DNA repair factors in a range of human diseases. | null | HRCS22_03119 | 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS | BLOOD |
Medical Research Council | MRC | MICA: Development of Boron Doped Diamond Based Transcutaneous Blood Gas Sensors for Improved Patient Ventilation Status Monitoring and Control | Dissolved oxygen and carbon dioxide blood gas levels are key indicators of respiratory health and represent an important diagnostic test for illness severity. Current procedures nearly all involve a direct skin puncture, removal of the blood and analysis in a blood gas analyser. Low numbers of analysers in hospitals means access is limited and sampling frequency for the patient low. Limited sampling means that potentially life altering complications resulting from excessive or insufficient ventilation can be missed. To significantly improve medical outcomes, this project will develop transcutaneous sensors, which sit on the skin and enable continuous monitoring of respiratory gases. Whilst there are limited transcutaneous devices available, take-up is lacking, primarily due to accuracy and sensor drift which necessitates removal, recalibration and reattachment, often many times during use, an activity requiring trained personnel and takes up valuable time. Research in our group has focused extensively on the use of an inherently stable (thermal, chemical and electrochemical) material, boron doped diamond (BDD), for electrochemical sensing. We have demonstrated through surface engineering, controlled incorporation of very robust forms of sp2 carbon in microspot patterns, which activate the sensor towards dissolved oxygen and carbon dioxide over the range required for transcutaneous monitoring. We use voltammetry as the measurement method, where both gases can be detected in one scan. Having two signals in one scan also enables us to introduce methods of internal referencing to help mitigate against possible drift issues. Our method of blood gas analysis when combined with the robustness and stability of the BDD, helps moves the sensor technology towards higher accuracy and single calibration use with a smaller spatial footprint. All lead to a sensor which offers greater patient comfort, no risk of patient infection and significantly improved ease-of-use. | null | HRCS22_03129 | 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES | BLOOD |
Department of Health and Social Care | NIHR | NIHR Research Group on Patient-centred sickle cell disease management in sub-Saharan Africa (PACTS) | Sickle cell disease (SCD) is a genetic disorder affecting 2% of newborns in sub-Saharan Africa (SSA) where >70% of the global disease burden occurs. It is characterised by chronic anaemia, episodes of severe pain, progressive damage to organs (heart, lungs, brain, kidneys) and impaired growth and intellectual development. SCD has been declared a major public health priority by the WHO and UN. Without the clinical management ‘mainstays’ of infection prevention, hydroxyurea and blood transfusions, most SCD patients die before five years of age. In high-income countries most SCD patients can access these mainstays so they live a good quality life past middle age. _x000D_ _x000D_ We will first conduct a situational analysis and then undertake implementation and epidemiology research in Nigeria, Ghana and Zambia designed to overcome barriers preventing SCD patients accessing mainstays of care. Implementation and epidemiological research have been identified by our SSA partners and their governments as priorities in need of strengthening. Implementation research based on empowerment theory (3 PhDs, 1/country): teams in health facilities (6/country – using cycles of standards-based audit, and community-based teams comprising SCD patients/carers, health workers from the facility and community members (1/facility using participatory action cycles) will test out patient-centred solutions to improve access to SCD care mainstays. A realist evaluation will generate a programme theory about what solutions work, for whom, why and in what context. Epidemiology research (post-doc): geospatial mapping of representative facilities providing SCD care mainstays across our three SSA countries will provide information about accessibility, including costs. Impact of our research will be measured through changes in patient outcomes and in patient-centredness of care. _x000D_ _x000D_ Our new collaboration builds on existing relationships and is based on principles of equity, respect and fairness. It brings together a novel multi-disciplinary team of leading African and UK SCD researchers, co-led by two female professors. Our gender-balanced applicants have expertise in clinical SCD care (adult/paediatric), blood transfusion, social science, implementation research, public health, mapping, epidemiology, health communication, policy advice and journalism/public communication. Our UK lead is a global expert in capacity strengthening and our plan for this covers individuals and institutions’ grant management systems. To expand capacity for SCD implementation research in SSA we will recruit a post-doctoral researcher, three African PhD students and four research assistants and support them to ‘learn by doing’. Bespoke professional development opportunities (such as mentoring, courses) based on formal training needs assessments will be provided for all those involved in Group activities including grant management staff in partners’ institutions. An assessment of institutions’ grant management capacity against an established benchmark will identify priority gaps (e.g. lack of policies, career opportunities or research uptake) and inform implementation of institution-specific actions plans. _x000D_ _x000D_ Our dissemination and community engagement plans will use multi-format resources (social media, academic, policy briefs) to reach our target audiences (including SCD patients, their families and communities and policy makers) and provide training in SCD for a cohort of African journalists. | null | HRCS22_05149 | 7.1 INDIVIDUAL CARE NEEDS;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.1 ORGANISATION AND DELIVERY OF SERVICES | BLOOD |
Department of Health and Social Care | NIHR | The clinical benefits and cost-effectiveness and safety of haematopoietic interventions for patients with anaemia following major emergency surgery: a phase IV, multicentre, multi-arm randomised controlled trial: Peri-op Iron and EPO Intervention Study - POP-I | BACKGROUND TO THE RESEARCH_x000D_ Each year over 100,000 people over 60 years of age in the UK are admitted to hospital for lifesaving emergency operations. Two of the most common emergency operations are for hip fracture and severe abdominal problems. Many of these people have anaemia (a reduced number of red blood cells). Anaemia increases the risk of dying after surgery and those that do survive have a slower recovery, more complications, and therefore spend more time in hospital. Anaemia can be treated with drugs such as iron, but whether this improves survival and the general health of people who require an emergency operation is not known. _x000D_ _x000D_ AIM OF THE RESEARCH_x000D_ Our aim is to improve outcomes for people who are anaemic following emergency surgery, and to determine the cost-effectiveness of drug treatment for anaemia compared with usual care. One treatment option is a single injection of iron, given through a small drip. Another treatment option, that has been used in combination with iron, is a form of a naturally occurring substance called erythropoietin (known as EPO). This works in combination with iron to improve anaemia. Research in other groups of patients, such as those with heart and kidney problems, has shown that both treatments work very well. However, we do not know whether they would help patients recovering from emergency surgery._x000D_ _x000D_ These treatments also carry risks such as causing infection and blood clots. Both are also costly. Some of our research has shown that these treatments are increasingly being used in the NHS in patients undergoing emergency surgery. The absence of high-quality research to guide this practice may be causing harm to some patients and unnecessary costs to the NHS._x000D_ _x000D_ The James Lind Alliance is a national partnership of patients, clinicians and carers who look at research priorities. Improving patient care around the time of emergency surgery and the timely identification and management of patients with anaemia have been listed as Top 10 research priorities in anaesthesia, perioperative care and haematology. Our own patient involvement work has also highlighted that this research needs to be carried out. _x000D_ _x000D_ DESIGN AND METHODS USED_x000D_ We have designed a study to investigate whether treating anaemia after emergency surgery leads to people having more days at home after their operation. The study will recruit patients who have had different types of emergency surgery for abdominal problems or hip fracture. These patients will enter the study 2–10 days after their emergency operation and then assigned randomly (by chance) to one of three study groups: 1: usual care, 2: iron injection 3: iron + EPO injection. We will also measure quality of life, safety, and cost or savings associated with either of the treatments. _x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ Patient representatives have guided all elements of this research including: the identification of patients having emergency surgery, the outcomes that are most important to patients, the acceptability of the interventions, consent procedures and follow-up plan. Patients co-produced this plain English summary._x000D_ _x000D_ DISSEMINATION_x000D_ The study will start in January 2022 and run for 4 years. The results will be presented at scientific meetings and published in leading medical journals. We will work with our patient partners and relevant Royal Colleges to ensure rapid dissemination amongst healthcare professionals and changes to national treatment guidelines. | null | HRCS22_05372 | 6.1 PHARMACEUTICALS | BLOOD |
Department of Health and Social Care | NIHR | Randomised trial of Haploidentical Transplantation compared to standard of care for Adults with Sickle Cell Disease | Sickle cell disease (SCD) is one of the most common serious inherited conditions worldwide. It is a disorder in which red blood cells become sickle shaped in conditions of stress. The sickle shape is unable to pass through blood vessels easily, resulting in a blockage. Patients with severe SCD may have many complications of their disease. These include repeated severe episodes of pain requiring frequent hospital admissions and strong pain medication, chronic pain, stroke, chest problems, increased risk of infection, impairment of brain function, kidney failure, low red blood counts causing severe tiredness, and leg ulcers. While advances in care have occurred in recent years, SCD is still associated with shortened life expectancy and early death. In addition, quality of life for those with severe SCD is affected with many patients suffering impacts on self-esteem, relationships, education and employment. Given the chronic nature of SCD, patients need to use significant NHS resources due to high need for medical care and hospital admissions. Standard treatment is limited, with regular blood transfusions and a drug called hydroxycarbamide the only options available. These treatment options do not offer cure and many patients will have complications of SCD while receiving these treatments._x000D_ _x000D_ Stem cell transplantation (SCT) is a procedure where healthy cells from a matched donor are given to a person with a blood disease. These healthy cells have the ability to re-populate the blood producing system and replace abnormal sickle cells. SCT is funded in the UK for children with cure estimated to be above 90%. Due to concerns about side effects of SCT, it has not been offered to adults. More recently, researchers have developed SCT protocols showing that SCT can be carried out safely in adults with high cure rates when receiving SCT from a 100% matched sibling. Patients can also receive SCT from relatives who are a 50% match, for example, from a sibling with whom they share one parent. This known as haploidentical (haplo) SCT. It is an important option as most patients do not have a 100% matched sibling. Initially there were concerns that haplo SCT would not work due to high rejection rates (this means that abnormal sickle cells were not replaced after receiving SCT), however recent research and new protocols mean it is now possible for haplo SCT to be done without rejection. The NHS has agreed funding for 100% sibling match SCT, however as most patients will not have a sibling donor, they will not have this option. The patient and public response to the NHS funding proposal suggested research into haplo SCT be considered. Therefore, we propose this clinical trial of haplo SCT compared to standard care. In this trial, 50% of patients would have SCT and 50% of patients would receive their normal care. _x000D_ _x000D_ The aims of this trial are to:_x000D_ - Assess whether haplo SCT is safe, show if haplo SCT improves outcomes such as frequency of pain episodes, quality of life, reduces the need for blood transfusions, and admission to hospital_x000D_ - Assess whether the cost of haplo SCT costs is less for the NHS than the current treatment_x000D_ _x000D_ In summary, current evidence suggests that haplo SCT could offer a curative treatment option, however this is not funded for adults in the UK at present due to lack of robust research. This research proposal will enable us to answer outstanding questions and then offer haplo SCT as a treatment option with the possibility of a cure for people living with sickle cell disease. | null | HRCS22_05500 | 6.2 CELLULAR AND GENE THERAPIES | BLOOD |
Department of Health and Social Care | NIHR | Artificial intelligence systems to improve the safety, efficiency and clinical outcomes of blood transfusion by the precise genetic matching of patients to blood units | Each year, 1.4 million units of blood are donated, providing transfusion treatment to over 700,000 NHS patients. Transfusion can be life-saving for patients with cancer or inherited red blood cell disorders or after blood loss caused by trauma or childbirth. The formation of antibodies against red blood cell antigens (sensitisation) is a well recognised complication of blood transfusion, arising from donor antigens mismatched to the patient. Once sensitised, further transfusions of blood must be matched very carefully or the patient's body may destroy the donated blood, leading to severe illness or even death. Sensitisation is especially common in patients with sickle cell disease who are dependent on transfusion. 17% of the sickle cell disease patients requiring transfusion in the UK have developed antibodies.[1] These patients are overwhelmingly of African ancestry and it can be very difficult to identify compatible blood for them under the current system of provision, because some blood types common in Africa are very rare in the NHSBT donor population, which is largely of European ancestry. We have developed an affordable DNA-test that can measure the blood types of all the human blood groups, which we are accrediting for clinical use. This test will allow NHSBT to measure the complete blood types of hundreds of thousands of blood donors and allow patients to be matched precisely to donated blood, whatever the ancestry of the donor. We seek support to prototype the AI algorithms required to implement precision blood matching routinely in the NHS. This includes algorithms to: translate measured genotypes into blood types ( bloodTyper ), identify the best matched units of blood for patient transfusions ( bloodMatcher ), optimise the mix of blood types in NHSBT stock by prioritising donor invitations ( bloodStocker ), link hospital and NHSBT computer systems to allow the automatic matching and ordering of blood ( bloodLinker ). | null | HRCS22_05946 | 7.3 MANAGEMENT AND DECISION MAKING | BLOOD |
End of preview.
Data Selection & Splitting
- Source: HRCS 2014, 2018, and 2022 direct award datasets.
- Quality Filtering:
- Only human-coded abstracts were included.
- Records with abstracts shorter than 75 characters were removed during preprocessing to ensure the model had sufficient text to learn from.
- Train/Test Split: The Test Set was isolated using only 2022 data to provide a modern performance benchmark.
Training Data Deduplication
To prevent the model from over-fitting on near-identical entries, a robust deduplication pipeline was implemented:
- Vectorization: Character-level TF-IDF vectors were generated from training titles using word-boundary character n-grams (length 3–5).
- Similarity Analysis: Near-duplicate titles were identified using a Cosine Similarity threshold of more than or equal to 0.85.
- Clustering: Records exceeding this threshold were grouped using a connected-components graph algorithm.
- Selection: Only the first occurrence in file order from each group was retained in the training pool.
Leakage Prevention (Train vs. Test)
To ensure the test set provides a truly unseen and honest evaluation, the following steps were taken:
- Shared Feature Space: The TF-IDF vectorizer was fit on the combined set of training and test titles.
- Cross-Set Comparison: Any training record with a Cosine Similarity threshold of more than or equal to 0.85 to any record in the test set was permanently removed from the training pool.
- Test Set Integrity: The test set itself was deduplicated using exact title matching only (no fuzzy matching applied).
Limitation: Short, highly generic grant titles (e.g., "Studentship") may have been deduplicated in the training set due to the similarity threshold.
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