NIHRDataInsights/HRCSData huggingface dataset:
Title: Advanced in-vitro and in-silico models to predict and prevent deep venous thrombosis
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Deep vein thrombosis (DVT) is a life-threatening and debilitating condition where blood clots form within the deep veins (e.g. the femoral vein in the leg). These clots can become unstable and cause fatal conditions such as pulmonary embolism (PE). DVT and PE combined cause 25,000 deaths annually in the UK. At the moment, it is impossible to perform early prediction of DVT and the pathology is only diagnosed once the symptoms present themselves. Typically, this happens during the triage stage and relies mostly on the ability of the operator to identify a thrombus with a Doppler machine. If a thrombus is unstable, the only solution is an emergency surgery to remove it. As a result, many patients with DVT symptoms are treated with anti-coagulants as a preventive approach although the actual number of confirmed DVT cases is just a small fraction of the total suspected. The need for a prediction tool is widely recognised. Such a tool will not only help identify and potentially help save the lives of those at risk from thrombosis but could also reduce the use of dangerous anti-coagulants for the majority of the treated patients that do not need them. With this project, we aim to investigate and understand the predictors of DVT based on a novel closer-to-reality in-vitro and in silico model developed by reproducing the anatomy of animal models, in particular mouse deep veins, available in literature, in order to reduce their unnecessary use.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD
Title: A novel in vitro reporter system for blood stem cell activity
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Blood stem cells (or Haematopoietic Stem Cells, HSCs) are the fundamental component of regenerative medicine applications involving the blood and immune system. HSC transplantation


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: DUTOSA: building a Data-driven cUlture in The bloOd Supply chain in nigeriA
Funder: The British Academy

Abstract: DUTOSA project aims to develop a framework for improving data-use culture in the blood supply chain in Nigeria. In Nigeria, the demand for transfusion often exceeds the supply availability of blood and blood products, which are scarce commodities. This contributes to increased mortality rates, poor patient experience and poor health outcomes. A recent study shows that 44% of the women who die annually in Nigeria from excessive blood loss during childbirth, do so because maternity units often lacked blood products (Sageer, et al. 2019). The blood supply problem is compounded by a lack of data-use culture in the healthcare system, which results in poor supply chain visibility, process inefficiency and waste. In response to this challenge, DUTOSA will support Nigeria to boost more data-driven decision making, towards achieving the health-related targets for Sustainable Development Goals (SDG 3).


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: BLOOD
Title: Gene Therapy for Congenital Factor VII Deficiency; Final IMPd/IND Enabling Studies
Funder: LifeArc

Abstract: This study aims to move forward the development of a cutting-edge gene therapy approach for severe factor VII deficiency (SF7D), a life-threatening bleeding condition characterised by a deficiency of clotting factor VII – a protein essential for the blood to clot normally. The condition is linked to a recessive chromosome and is thought to affect around 1 in 500,000 people. The liver is one of the prime targets for gene therapy to correct defects in a variety of clotting factor genes, but gene therapy for this condition has not been explored due to its rarity and the perceived difficulty in intervening early enough in life to prevent permanent organ damage and death. This project is using the same virus vector platform technology that supported successful gene therapy in people with a related condition, haemophilia B, by mediating the continuous expression of a transgenic protein in these patients. The team has developed a more potent form of the virus vector containing a codon optimised human FVII cDNA under the control of a small liver-specific promoter. The new virus vector has shown to greatly increase the transgene expression and preclinical data has enabled the potential therapy to be granted an orphan drug designation (ODD). This study proposes/will undertake phase I/II clinical trials of the orphan drug in adults, potentially followed by trials in adolescents and children. The team has established a wide-reaching clinical research network which, together with swift trial design and access to clusters of patients, improves the prospect of successful gene therapy for the condition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Production of expanded autologous regulatory T cells to treat patients with refractory aplastic anaemia in a phase I dose study
Funder: LifeArc

Abstract: The team’s earlier research had shown that patients with refractory aplastic anaemia (AA) have fewer T regulatory cells (Tregs) which dampen down the abnormal cells that destroy bone marrow stem cells. The research team then used new technology to expand the Tregs from AA patients “in vitro”, confirming that they prevent the immune system from attacking the bone marrow stem cells. Following these laboratory results, researchers plan to start a phase I/II clinical trial for AA patients who have not responded to standard treatments, examining the safety of administering Tregs that have been expanded in vitro back into the donor patients. This is a single site, open-label, phase I/II clinical trial at King’s College Hospital / King’s College London. This form of cellular therapy for AA is a world first. The team will study the changes in the immune system in detail and determine if healthy bone marrow stem cells regenerate following administration of the expanded Tregs. The use of expanded ‘autologous’ Tregs is currently being evaluated in other autoimmune disorders such as type I diabetes mellitus, multiple sclerosis, Crohn’s disease and systemic lupus erythematosus – as well as in organ transplantation. Results so far indicate that this treatment is safe and may improve outcomes in these diseases. The project outcome will be the availability of data to demonstrate how safe this potential treatment is and the optimal dose to be given.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Evaluation of lightweight fibreglass heel casts in the management of ulcers of the heel in diabetes
Funder: Department of Health (England)

Abstract: Lightweight fibreglass heel casts are thin enough to fit inside usual footwear and observational data suggest that their use is accompanied by a marked improvement in the rate of healing as well as a prompt reduction in discomfort in a percentage of patients. Patients with heel ulcers from 25-30 participating centres will be randomised to receive treatment with or cast or not and will be reviewed each two weeks until healing or for 24 weeks.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: BLOOD
Title: The Age of Blood Evaluation Study (ABLE)
Funder: Chief Scientist Office (Scotland)

Abstract: DESIGN: Double-blind multicentre parallel group randomized controlled clinical trialSETTING: 10-12 general adult ICUs.TARGET POPULATION: Adult critically ill patients in ICU who: have had a request for a first Red Blood Cell (RBC) unit transfusion during the first 7 days of ICU admission and have an anticipated requirement for ongoing mechanical ventilation exceeding 48 hours. Exclusions include: age < 16 years; previous enrolment in ABLE; already transfused RBCs during this admission; terminal illness; routine cardiac surgical care; no RBCs available with a storage time of 7 days or difficult cross match; patient objection to RBC transfusion.HEALTH TECHNOLOGY ASSESSED: We will compare: 1) standard issue RBCs with 2) RBCs stored 7 days or less. Post-randomisation group allocation will be maintained for the remainder of the patient’s hospital stay (up to 90 days). The storage age of RBC units will be concealed from clinical and ICU-based research staff and patients using study specific blinding stickers.MEASUREMENT OF COSTS AND OUTCOMES: Primary outcome: 90-days all-cause mortality. Secondary outcomes: 1) mortality rates at hospital and ICU discharge and at 30-days 6 and 12 months; 2) differences in organ failures assessed using the multiple organ dysfunction (MODS) scores; 3) differences in nosocomial infections; 4) adverse events including transfusion reactions. We will also measure HRQoL at 6 and 12 months using EuroQol EQ-5D and health resource use with questionnaires. These will be used to conduct a health economic analysis.SAMPLE SIZE: The overall trial is designed to detect an absolute risk reduction of 5% from 25% to 20% (RRR 20%) which requires a total of 2510 patients. We plan a priori defined subgroup analyses of patients with: 1) cardiovascular diseases; 2) multiple trauma; 3) severe sepsis; and 4) acute respiratory distress syndrome. We will recruit 500 patients in the UK.


Research activity codes: 6.4 SURGERY
Health categories: BLOOD
Title: Clinical Trials in Transfusion Medicine
Funder: Medical Research Council

Abstract: The aim of the programme of clinical studies in transfusion medicine is to improve evidence base for safe and appropriate use of blood, blood components and alternatives to blood in order to reduce unnecessary exposure to hazards of transfusion, underpin blood service planning for blood component provision, and make best use of a scare donated resource. It is a collaboration between the MRC Clinical Trials Unit and NHS Blood and Transplant, a Special Health Authority with the remit to provide a reliable, efficient supply of blood, organs and associated services to the NHS.|Summary of Studies Currently Open to Recruitment:|TOPPS - Trial of Prophylactic Platelets |Platelet transfusions are given prophylactically to reduce the risk of bleeding in thrombocytopenia. This RCT compares prophylactic vs no prophylactic platelet transfusions in patients with haematological malignancies, & aims to demonstrate that a policy of not giving prophylactic transfusions is not inferior to the standard prophylactic policy, with respect to the proportion of patients developing moderate or severe bleeding.|TAPS - Transfusion Alternatives Pre-operatively in Sickle cell disease |Currently, people with Sickle-cell disease are routinely given a top-up blood transfusion before they undergo surgery in the belief that this helps recovery. However, there is no evidence that this practice is of benefit. This RCT aims to compares pre-operative transfusion vs no transfusion in sickle cell patients undergoing low/medium risk elective surgery. The total number of patients (from the UK and the US) to be recruited to this trial is approximately 400. |PPIP - Platelet Process Improvement Project |The current shelf-life of platelets is 5 days and this short shelf life can cause difficulties with stock control and availability of platelets. As long as no bacterial contamination can be identified, platelet packs can be kept for 7 days. Evidence from laboratory studies show that 7 day platelets function adequately. This trial aims to show that this result is corroborated when platelets are transfused to prevent and treat haemorrhage in thrombocytopenic patients. |PRISM - Trial of Prion-Filtered vs. Standard Red cells in Surgical and Multi-transfused patients |Study A: A non-randomised controlled trial aims to assess the safety of blood that has been passed through a filter to reduce prions (proteins) thought to cause vCJD. |Study B: This double blind RCT that will test the safety of filtered blood in 340 haematology/oncology patients who require regular transfusions for their medical care.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: BLOOD
Title: MECHANISMS IN HAEMOPOIETIC DIFFERENTIATION: INSIGHTS FROM NOVEL LOCI IN GENETIC THROMBOCYTOPENIA
Funder: Medical Research Council

Abstract: 1. Recruitment of index cases I will recruit patients at SW England haemophilia centres if their registration diagnosis is genetic thrombocytopenia. I will also identify women from obstetric haematology clinics if their platelet (PLT) count is <80x10^9/dL at booking and at all subsequent tests in pregnancy. I will exclude women if any PLT count outside pregnancy is within reference interval or if acquired thrombocytopenia is detected using a pre-specified test panel (eg. autoantibody screen, lupus anticoagulant). I will invite eligible women to participate only with further evidence of genetic thrombocytopenia (eg. family history, high PLT volume). After informed consent, the Cambridge BioResource for Rare Diseases will collect demographic and clinical phenotype data and will store DNA samples. 2. Identification of novel loci I will exo-seq DNA using the Roche/Nimblegen SeqCap EZ Human Exome Library v3.0 which covers >98% of 198,334 exons in the 64Mb CCDS regions gene set, expanded by 32Mb to capture most annotated regulatory elements in megakaryocytes. Exo-seq will be at the Eastern Sequence and Informatics Hub using Illumina-HiSeq analysers. I will work with the MRC Biostatistics Unit to identify causative variations using the UK10K and other resources to eliminate non-pathogenic common variations. Based on pilot studies for GPS and TAR, significant genome-wide P values of association were observed with exo-seq results of 10 cases only. The power of my sample of 150 to identify a novel locus will be enhanced by data sharing with the BRIDGE exo-seq programme of 1000 cases which is sufficiently powered to yield several new loci and will increase case finding for each locus. 3. Functional analysis of a locus I will perform deep phenotyping of index cases, gene knockdown and phenotyping in zebrafish and gene knockdown and TALEN-modification of iPSC using protocols developed by my collaborators in Cambridge and Bristol.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Development of a lentiviral gene therapy vector for treatment of haemophagocytic lymphohistiocytosis (HLH) due to perforin deficiency
Funder: Medical Research Council

Abstract: HLH is a severe disorder of immune dysregulation characterized by failure of effector cell cytotoxicity in which affected individuals suffer multiorgan complications due to hypercytokinemia and histiocytic infiltration. Mutations in the perforin gene give rise to the most common form of HLH. Treatment of this disease is currently limited to the control of infectious triggers and chemotherapeutic regimes to control the initial dysregulation, but permanent correction can only be achieved by allogeneic hematopoietic stem cell (HSC) transplantation which has high mortality in mismatched donor transplants. The aim of this project is to develop a safe and effective lentiviral gene therapy vector encoding the perforin gene that can be used to modify autologous HSCs for treatment of perforin deficient HLH or to modify effector T and NK cells to be used to control disease activity in patients refractory to conventional chemotherapy. Initial experiments show that introduction of the correct copy of the perforin gene into HSCs can restore the T and NK cell defects seen in perforin deficient mice and that reconstituted mice are protected against development of HLH after viral challenge. These initial experiments provide a proof of principle for this gene therapy approach and pave the way for further studies to make this a clinical reality. We now seek further funding to undertake translational studies to develop and test a lentiviral vector that can be used in a Phase I/II clinical trial. We need to test the immunotoxicity and genotoxicity of this system and test whether the efficacy is long term and robust. A successful outcome will be data that confirms vector safety and efficacy and allow us to generate a clinical grade vector for use in clinical studies. This will be the first clinical gene therapy study for this group of disorders and extends the applicability of gene therapy for diseases of the haematopoietic system.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Improvement of Pain and Quality of Life in Patients with Sickle Cell Disease with Nocturnal Oxygen Therapy or Auto-adjusting Continuous Positive Airways Pressure: a feasibility study
Funder: Department of Health (England)

Abstract: Oxygen saturation (SpO2) often decreases at night in patients with sickle cell anaemia (SCA) and is implicated in complications such as frequent pain, stroke and impairment in cognitive function, which reduce quality-of-life. Maintaining nocturnal SpO2>94% should improve these outcomes. Our proof-of-concept randomised controlled trial (RCT) of auto-adjusting continuous positive airways pressure (auto-CPAP) in children showed improvement in attention and pain frequency. We also have feasibility and safety data for overnight oxygen. However it is not clear whether either overnight oxygen or auto-CPAP is better tolerated and there are no adequately powered trials to determine the efficacy of either intervention. This is a three arm parallel feasibility RCT with 2 parts: (1) quantitative evaluation of feasibility, adherence and effect of treatment arm on endpoints including pain, cognitive function and quality-of-life and (2) qualitative analysis of patient acceptability of the interventions and overall experience. Part 1 Quantitative Research Months 6-21 Eligible patients will be randomized into (i) overnight auto-CPAP or (ii) overnight continuous oxygen therapy or (iii) no overnight respiratory support (standard treatment). In groups (i) and (ii) the aim will be to maintain minimum SpO2>94%. Adherence will be defined as using the equipment for at least 4 hours per night 7 nights out of 10 for 6 months i.e. at least 126 nights. Potential participants will be identified by healthcare professionals from the participating centres. Consenting participants will undergo baseline tests in the local CLRN, including full blood count undertaken as part of safety monitoring, and overnight oximetry at home to determine the minimum SpO2 and the total sleep time (TST) with SpO2 Part 2 Qualitative Research Months 13-24 All participants participating in the study will be invited to take part in qualitative interviews about their experiences of the intervention and trial. Interviews will be conducted in patients’ homes (or over the telephone depending on the patient’s preference) within 2 weeks of their completion of the study or within two weeks from discontinuing the intervention for whatever reason. Interviews will be tape-recorded and fully transcribed. Thematic analysis will be used to identify emerging themes that comprehensively describe and provide insight into the experiences of patients and their carers. To enhance the credibility and validity of our interpretation, findings from these studies will be discussed in the research team and with our PPI co-applicant and fed back to participants who wish to comment on them.


Research activity codes: 6.7 PHYSICAL
Health categories: BLOOD
Title: Erythropoiesis in Health and Disease
Funder: Department of Health (England)

Abstract: "Blood for transfusion saves lives and is precious to the NHS. Erythropoiesis or making red blood cells is not only fundamental to human health and more specifically to the health of blood donors but also becomes abnormal in many patients requiring blood products. This programme will improve the health of blood donors and the blood supply by systematically analysing the published data, advancing our understanding on the basis of iron deficiency in blood donors and suggest how this may be predicted and prevented. It is now possible to grow red blood cells from a variety of cells including precursor or immature cells found in the umbilical cord of newborns and more remarkably from blood cells derived from adult skin cells. We will optimise the ability of these cells to make red blood cells and in doing so will be able to grow red blood cells from defined individuals with valuable blood types for helping to test blood groups and cross-match blood. Recapitulating the last phases of growth of red blood cells is surprisingly less well understood but we have developed the tools to understand how the final discoid red blood cells that circulate in our blood vessels are produced. We will optimise red cell production in the laboratory and see how these cells differ from red blood cells taken for transfusion. The early or mature red blood cells grown in the laboratory may be tested as new types of blood transfusion or replacement in the future. Finally, we will study a large group of patients who have lost the ability to make red blood cells normally and often become transfusion dependent. We will study why their bone marrow cells are unable to make red blood cells and see if we can define groups of patients whose disease is less serious than others and/or respond to treatment. This personalised or tailored approach to the definition of disease type and therapy promises more effective and cost-effective treatment in the future. This programme has been designed to study these issues in the context of the population of England & Wales and the impact of changes in practice to patients, the National Blood Service and the NHS: • What research evidence do we already have on iron deficiency in donors? • Why do some blood donors become iron deficient and how can we predict this? • What cells can we use to grow red blood cells in the laboratory? • Can we make large amounts of red blood cells in the laboratory? • Why can’t some people make enough red blood cells? • Can we predict which patients will respond to treatment? The work will be done by a large group of doctors and researchers across the NHS and Universities of Liverpool, Oxford and London over a five year period. The outputs of the programme may have a significant impact on the health of blood donors and patients and provide individualised and possibly more effective treatment for transfusion dependent patients with bone marrow disorders"


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.4 SURGERY
Health categories: BLOOD