NIHRDataInsights/HRCSData huggingface dataset:
Title: Optimisation of the manufacture of a homogeneous synthetic haemoglobin as a novel Oxygen Therapeutic / Blood Substitute
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Generating platelets in vitro for the clinic: optimisation and added clinical efficacy
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Human blood stem cell expansion: Empowering new technology for stem cell medicine
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: UNDERSTANDING MOLECULAR MECHANISMS UNDERLYING DEVELOPMENT OF HIGHLY REGENERATIVE HUMAN HAEMATOPOIETIC STEM CELLS
Funder: Medical Research Council

Abstract: 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


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: A molecular and structural approach to understanding interstrand crosslink incision by the Fanconi anaemia DNA repair pathway
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: MICA: Development of Boron Doped Diamond Based Transcutaneous Blood Gas Sensors for Improved Patient Ventilation Status Monitoring and Control
Funder: Medical Research Council

Abstract: 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.


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: BLOOD
Title: Avatrombopag in combination for treating chronic immune thrombocytopenia [ID3838]
Funder: Department of Health and Social Care

Abstract: Immune thrombocytopenia (ITP, also called immune thrombocytopenic purpura) is an autoimmune condition characterised by increased platelet destruction and, in some cases, inadequate platelet production.[1] Platelets are made in the bone marrow and they travel through blood vessels and stick together to stop any bleeding that may happen if a blood vessel is damaged. ITP can result in low platelet counts and bleeding. In a blood test, a normal platelet count (concentration) is between 150 and 450 × 109 per litre.[1],[2] Bleeding does not usually occur until the platelet count is below 30 × 109 per litre.[2] ITP is defined as persistent 3 to 12 months after diagnosis, and chronic when it lasts longer than 12 months.[1]_x000D_ _x000D_ The UK incidence of adult ITP is estimated to be between 1.6 to 3.9 per 100,000 adults per year.[3] People with ITP may be asymptomatic or have symptoms including fatigue, anxiety, spontaneous bruising, mucosal bleeding and, in severe cases, gastrointestinal or intracranial bleeding. Diagnosis is based on excluding other possible causes of the symptoms.[4]_x000D_ _x000D_ Treatment for ITP is usually required when the platelet count is below 30 × 109 per litre.[4] Treatment is typically initiated with rescue therapies such as low-dose corticosteroids and intravenous immunoglobulins. People who are intolerant or refractory to these treatments can use active therapies such as mycophenolate and rituximab, and thrombopoietin receptor agonists (TPO-RAs). Splenectomy is an option, but is rarely used in the UK.[4]_x000D_ _x000D_ NICE technology appraisals TA221 and TA293 recommend TPO-RAs (romiplostim and eltrombopag) for adults with chronic ITP whose condition is refractory to standard active and rescue therapies or those who are at high risk of bleeding and require frequent courses of rescue therapies._x000D_ _x000D_ References_x000D_ 1. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113(11):2386-2393._x000D_ 2. Lymphoma Action (2019) Thrombocytopenia (low platelets). Accessed December 2020._x000D_ 3. DR Terrell, LA Beebe, SK Vesely, BR Neas. 2010. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am. J. Hematol. 85:174– 180_x000D_ 4. BMJ Best Practice (2019) Immune thrombocytopenia. Accessed December 2020.

Lay abstract: To appraise the clinical and cost effectiveness of avatrombopag within its marketing authorisation for treating chronic immune thrombocytopenia.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Investigating macrophage behaviour and interactions in normal and pathophysiological erythropoiesis
Funder: Wellcome Trust

Abstract: Macrophages are known to be intrinsically involved in nurturing erythroid cells within the bone marrow. They regulate and enhance erythropoiesis, the production of Red Blood Cells (RBCs), through maintenance of the haematopoietic stem cell (HSC) niche and erythroblastic islands (EBIs). Understanding the cellular interactions involved in EBI formation and maintenance is crucial for investigating disease and improving in vitro erythropoiesis. Polycythemia Vera (PV) is a disease involving increased differentiation of progenitor cells towards the RBC lineage, and subsequent overproduction of RBCs. The genetic component, caused by a single acquired mutation in the tyrosine kinase JAK2, is well established. However, current treatments experience issues with resistance and intolerance, and the involvement of other cell types remains largely under-studied. Importantly, recent studies have implicated a role for macrophages in PV. I aim to further elucidate the molecular basis and cellular interactions that underly the role macrophages play in normal erythropoiesis and PV. CD14+ macrophages from PV and normal patients will be isolated to investigate phenotypic changes, including secreted cytokine profile, proteomic profile and mutations in JAK2. Image analysis will be conducted to probe whether there are changes in interactions between macrophages, progenitors, and erythroblasts within the normal and disease contexts.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Promoting an Adult Phenotype in Erythroblasts and Megakaryocytes derived from Human Pluripotent Stem Cells through a Forward Programming Approach
Funder: Wellcome Trust

Abstract: Red blood cells (RBCs) and platelets are important cells in the blood required for oxygen delivery and blood clotting, respectively. Having too few of these cells, which can be caused by things such as cancer treatment, can lead to severe health problems. Although this is treatable using voluntary blood donations, in coming years more donations will be needed. Alternative options must therefore be developed. In answer to this, the Ghevaert group has developed a method (known as 'forward programming', or 'FOP') to artificially produce RBCs and platelets from stem cells in the lab. Unfortunately the cells produced by FOP are less functional than the adult cells found in our bodies, meaning that improvements must still be made. Using a computer program, I will redesign FOP so that it produces more functional RBCs and platelets from stem cells. This redesigning will involve changing the core ingredients used to drive FOP, so that FOP is more likely to produce adult cells. I will also investigate why it is so difficult to produce adult RBCs and platelets from stem cells. Consequently this work will guide future research in a more informed direction, and may provide a viable alternative to donated blood products.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Haematopoietic stem cell therapies: gene addition, editing, and molecular analysis
Funder: Wellcome Trust

Abstract: We are pioneering the development and application of haematopoietic stem cell (HSC) gene therapy for rare disease, including primary immunodeficiency and inborn errors of metabolism. Remarkable progress has been made over the last two decades, with notable clinical success in a number of different diseases, and transfer of some into the commercial biotechnology sector. Our overall research aim is to create a flexible pipeline of research from gene discovery through disease biology to translation of novel gene and cell therapies. We will address the following areas. 1) enhancement of therapeutic translation for increased numbers of tractable disease targets 2) development of state-of-the-art manufacturing processes to ensure reliability of effect and safety, alongside use of novel technologies to increase efficiency 3) interrogation of haematological and immunological reconstitution in patients as a platform for understanding efficacy and underlying biological mechanisms 4) development of gene editing platforms for HSC modification where semi-random gene addition may be undesirable or ineffective 5) Development of new tools to enhance gene editing in HSC 6) evaluation of novel technologies for detecting on and off-target gene editing aberrations and pre-clinical/clinical assessment of safety 7) application of novel reduced toxicity conditioning strategies for HSC engraftment in gene therapy protocols.

Lay abstract: We are developing new treatments for rare diseases in which existing options are either dangerous or not completely effective. In particular we are interested in using gene therapy for patients with inherited problems of the blood and immune system. Over the last 20 years ever increasing numbers of patients have shown remarkable clinical effects following gene therapy, and industry is developing some of these as licensed medicines. We have pioneered some of this work, and in this application aim to improve technology in order to enhance safety and ensure that effectiveness is reliably achieved in all patients. Furthermore, we want to make sure that the treatments can be extended to a wider number of patients, and to an even broader number of diseases. Eventually our hope is that these will become part of the standard care pathway for patients with these devastating disease.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Development of an innovation to secure peripheral intravascular cannulas: improving care, minimising exposure, conserving PPE and saving cost.
Funder: Innovate UK

Abstract: Intravenous cannulas are the most commonly used patient device in modern medicine. The majority of COVID-19 patients will receive an IV cannula to administer drugs, fluids and antibiotics. IV cannula insertion takes 20 minutes of HCW time. However, up to 50% of devices fail before meeting their clinical need. Patients admitted to intensive care routinely undergo cannulation of the radial artery. These cannulas also frequently fail and need replacing. If the majority of the UK population is affected by COVID-19, cannula failures could lead to millions of reinsertions, unnecessary HCW exposure and PPE use. An SME is developing a low-cost device that is worn by patients to protect and secure cannulas in order to reduce failure rates, improve care, reduce waste and minimise unnecessary HCW exposure to COVID-19\.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: BLOOD
Title: Development and Characterization of a Novel Endothelialized in vitro Model of Human Atherothrombosis
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Cardiovascular disease is the leading cause of death globally, responsible for 17.7 million deaths a year, 80% of which are caused by heart attacks and strokes. These arise when atherosclerotic plaques, in coronary or carotid arteries rupture or erode releasing tissue factor and exposing components of the blood vessel wall, which trigger thrombosis (atherothrombosis). The development of atherothrombosis is a complex and highly regulated process involving the blood vessel wall, platelets, endothelial cells, and plasma proteins. To investigate the mechanisms that lead to atherothrombosis, and develop more effective, antithrombotic treatments, appropriate experimental models are crucial.


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