NIHRDataInsights/HRCSData huggingface dataset:
Title: Prenatal stem cell gene therapy for Wilson's Disease using amniotic fluid stem cells.
Funder: Wellcome Trust

Abstract: Genetic (inherited) diseases can affect babies before birth, and result in significant long-term disability. Such conditions, can now be diagnosed duringearly pregnancy, and following diagnosis parents may have to make the difficult choice of either terminating the pregnancy or giving birth to an affected child. An alternative would be to correct the genetic problem in these babies before birth, to avoid development of long-term consequences of the disease. Wilson's disease is an inherited disorder that is associated withprogressive injury to the liver and other organs. It is caused by damage to a specific gene, and might be amenable to treatment during pregnancy. We would like to use a mouse model of Wilson's disease to test a new approach for treatment before birth. We propose to collect immature cells from within the amniotic sac, correct the genetic problem in the laboratory, and then inject these cells back to the baby mice for therapy. The injected cells would then be expected to multiply, mature and restore function in the liver of mice affected by Wilson's disease. This method of treatment during pregnancy may besafer and more effective than others, and successful outcome of the proposed programme of work may lead to new therapies for Wilson's and other genetic diseases in human beings.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;ORAL AND GASTROINTESTINAL
Title: Investigation of the pathophysiology and in-utero treatment of gastroschisis-related gut dysfunction.
Funder: Wellcome Trust

Abstract: Gastroschisis is a belly wall defect arising during pregnancy resulting in bowel lying outside the abdomen in contact with irritant amniotic fluid. At birth the bowel is inflamed and sluggish resulting in poor feeding requiring drip feeds. However, the cause of sluggish bowels is poorly understood. Our previous research showed that before birth the amniotic fluid of gastroschisis fetuses is inflamed. Other researchers found in animal models and a human gastroschisis case there are lower than nor mal number of a specialised nerve cell called the interstitial cells of Cajal (ICC), which are essential for gut movement. I hypothesise that bowel inflammation causes ICC to develop poorly resulting in sluggish bowels and this could be prevented. I aim to 1) study the development of nerve and muscle development in gastroschisis; 2) investigate how inflammation effects ICC development; 3) try to improve ICC development in gastroschisis; 4) determine how ICC numbers effect gut movement and abs orption; 5) Investigate what components are present in amniotic fluid of gastroschisis babies and how it relates to sluggish bowels. These aims will be addressed through human and animal studies using techniques to look at bowel cells, amniotic fluid proteins and gut movement/absorption.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;ORAL AND GASTROINTESTINAL
Title: Molecular bases of congenital bladder disease: the urofacial syndome (UFS)
Funder: Medical Research Council

Abstract: The genetic bases of lower urinary tract (LUT), especially bladder, malformations are poorly defined. Moreover, current clinical interventions for congenital bladder disorders, such as surgery to refashion the renal tract and fetal termination, do not target the primary causes of disease. The urofacial syndrome (UFS) is an autosomal recessive disease in which urinary bladder muscle functions abnormally. We were the first to describe mutations in two genes, HPSE2 (a heparanse inhibitor) and LRIG2 (an integral membrane protein), in a proportion of affected individuals. We have published preliminary data that these genes code for proteins located in nerves which invade developing bladders. UFS is a discrete clinical disorder but its LUT abnormalities, including bladder dyssynergia and vesicoureteric relfux of urine, overlap with features of Hinman-Allen syndrome, itself at the severe end of a spectrum of LUT disorders including primary VUR which affects 1% of infants and is often familial. We will use UFS as an exemplar to not only understand the pathogenesis of a specific LUT disease but also to derive insights into other LUT disorders. We will address the following related questions and hypotheses. 1. Is there a neurogenic basis for UFS, and what is its nature? 2. Can we generate animals to model the anatomical, physiological, molecular and cell biology features of UFS and can these models be used to test potential therapies such as heparanse inhibitors and growth factors? 3. Do other UFS genes exist and are UFS genes relevant to other LUT malformations? In a separate project, we plan to generate induced pluripotent stem cells from UFS patients and derive neural tissues from them. Thus, we will be well-positioned to apply functional insights from the current project to test similar therapies on human cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RENAL AND UROGENITAL
Title: Can magnetic resonance imaging scan replace or triage the use of laparoscopy in establishing diagnosis among women presenting in secondary care with chronic pelvic pain?
Funder: Department of Health (England)

Abstract: Chronic Pelvic Pain (CPP) is defined as pain in the pelvic and lower abdominal region that lasts for 6 months or longer. In primary care the annual prevalence of CPP is 38/1000 in women aged 15-73 a rate comparable to that of asthma (37/1000) and chronic back pain (41/1000). No effective management policy exists for CPP. At present there is a wide variation in clinical practice concerning diagnosis and management of CPP. This wastes both patients’ time and NHS resources. For example the diagnosis of endometriosis may be delayed by over 8 years after first presentation with CPP symptoms potentially demoralising the patient and missing the opportunity to improve their quality of life through early effective treatment and may provoke women to seek having a hysterectomy with its inherit risks and consequences. There is a perception that diagnostic laparoscopy an invasive expensive and potentially risky procedure is used far too frequently in the NHS as a significant proportion of patients have no pathology identified. Over 40% of laparoscopies are done solely for the diagnosis of CPP. The aim of this study is to estimate the accuracy of an alternative non-invasive and cheaper test - Magnetic Resonance Imaging (MRI) scanning - in diagnosing common underlying pathologies causing CPP and hence the proportion of women who could avoid a laparoscopy with adequate certainty. Three hundred and forty women referred for a diagnostic laparoscopy for CPP will be asked to have a MRI as well. The three main strategies will be compared are:1.History examination ultrasound and laparoscopy 2.MRI scans as an adjunct to laparoscopy3.MRI as a replacement for laparoscopy


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RENAL AND UROGENITAL;ORAL AND GASTROINTESTINAL
Title: Cellular and molecular control of human embryonic alveolar development: towards lung regeneration
Funder: Medical Research Council

Abstract: Interruptions in normal embryonic lung development caused by premature birth lead to a life-long decrease in respiratory capacity. We will study the cellular and molecular mechanisms underlying human embryonic alveolar development, and develop improved in vitro alveolar models, as the first steps to improving outcomes for premature neonates. Our preliminary data show that there are numerous differences in the molecular regulation of mouse and human embryonic lungs. We will therefore focus our research directly on human embryonic lungs and a human embryonic lung organoid system that my lab has developed. We will reconstruct the alveolar epithelial cell lineage in human embryos, and our organoid system, using single cell RNA-seq. A major focus of the bioinformatics approaches will also be analysis of epithelial cell signalling pathways. The human embryonic lung epithelial organoid system that we have developed will be used to screen for combinations of signalling molecules that are sufficient to promote alveolar epithelial cell differentiation. We will use wholemount antibody staining to identify the mesenchymal cell populations participating in human alveolar development. Lentiviral-mediated lineage-labelling in multiple single cells in lung slice cultures and kidney capsule grafts, followed by quantitative analysis, will be used to determine the mesenchymal cellular hierarchy. The organoid system will be combined with specific populations of mesenchyme and endothelial cells to determine cell-cell interaction nodes that control specific aspects of differentiation and morphogenesis. The organoid system will be further developed into a genetically-manipulable model for studying human alveolar disease. We will focus on using this to study contributing genetic factors to BPD and will also investigate its utility for other lung conditions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY
Title: Delhi Air Pollution: Health aNd Effects (DAPHNE)
Funder: Natural Environment Research Council

Abstract: Delhi Air Pollution: Health aNd Effects (DAPHNE) DAPHNE is a consortium of doctors, scientists and technologists drawn from 9 institutions (six in India and three in the UK), to study the effect of air pollution in the city of Delhi on the health of pregnant mothers and their new-born children, and asthmatic adolescents. This group is particularly vulnerable because of their greater intake of air with respect to the body weight, and an underdeveloped immunity system; and, also, the adolescents have greater outdoor exposure when travelling to school and during play times. In addition to estimating the amount of suspended particles and gaseous pollution inhaled by subjects using existing networks of stationary air quality monitors and satellite data, the project introduces novel devices worn on the person to measure exposure to suspended particles and noxious gases, and monitor their breathing rate and breathing effort when the subjects are out and about in their everyday lives. This will estimate the impact of air pollution on their asthma and how different levels of activity could contribute to changes in their condition. Biomarkers in samples of blood and urine taken from the subjects will be used as further evidence to estimate the effects of air pollution on changes in their well-being. Finally, a panel of stakeholders drawn from India and the UK will advise on how best the research results can be translated into interventions to help mitigate the effects for the benefit of the citizens of Delhi in the first instance, with potential for world-wide application in the future.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY
Title: Development of recombinant surfactant protein D therapy to prevent neonatal chronic lung disease
Funder: Medical Research Council

Abstract: Surfactant protein D (SP-D) is one of a family of collagenous lectins that play an important part in pulmonary innate immunity. They contain a collagen-like region and a C-type lectin domain, and bind carbohydrates in a calcium-dependent manner. The technology to be used in this application is based on the human protein, Surfactant Protein D (SP-D). A recombinant fragment of the molecule, rhfSPD, has been developed that maintains the relevant anti inflammatory properties of the native SP-D. This fragment consists of a carbohydrate binding domain, a trimerising neck region and a short segment of the collagen domain. The fragment has been crystallised and its structure solved. IP rights in rfhSP-D and its uses reside in the University of Southampton SP-D and rfhSP-D have well documented immunomodulatory and anti-inflammatory properties in the lung. Pre-clinical data show efficacy of rhSPD treatment in chronic inflammatory lung disease. Knock-out mice, lacking SP-D develop symptoms of COPD and emphysema relevant to chronic lung disease of infants which are correctable by treatment with recombinant SP-D. Efficacy of rfhSP-D has been demonstrated in multiple murine models of infectious (bacteria, viruses, fungi and parasites) and allergic lung inflammation triggered by fungal and house dust mite allergens. Pre-clinical data in large animal models (neonatal lamb) show that intervention with rhSPD reduces inflammatory biomarkers of neonatal chronic lung disease. The protein can be manufactured straightforwardly and we are currently in industrial process development to generate a robust GMP-capable manufacturing procedure. This will enable manufacture of the clinical batch to GMP for use in clinical trial. The route to market will be as Prescription Only Medicine (POM). This will require that preclinical toxicology and safety be completed and an initial phase I clinical safety dose escalation study performed in pre-term infants at risk of nCLD


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY
Title: MICA:The immunogenicity of combined pertussis-containing vaccine (Tdap) for HIV-infected pregnant women and their newborns-A Randomized Clinical Trial
Funder: Medical Research Council

Abstract: Maternal vaccination with Tdap is routine in high income countries and recommended by the WHO for low and middle-income settings. However, there is currently no evidence of efficacy in high HIV-burden settings, hampering vaccine implementation. This study aims to investigate the effect of maternal HIV infection on the immune response to tetanus, diphtheria, acellular pertussis (Tdap) immunization in pregnant women and will look at whether Tdap vaccination in pregnancy influences the infants' immune response following immunization with whole cell pertussis (wP) vaccine. We plan a phase IIb intervention randomised observer blind clinical trial of Tdap vaccine in pregnancy and wP vaccine in infancy at Mulago Hospital, Kampala in 94 HIV-infected and 94 HIV-uninfected women. Women will be randomised to receive either routine care (tetanus toxoid vaccine) plus Tdap or routine care vaccinations alone. We will collect baseline, 4 weeks post-vaccination and post-delivery blood from women and cord blood. We will follow infants until 18 weeks of age taking a final blood sample 4 weeks after 3 doses of wP vaccine. We will perform multiplex Luminex assays to determine antibody concentrations followed by avidity and serum bactericidal assays to determine antibody function, as it is known that HIV infection confers a hypergammaglobulinaemic but poorly functional antibody state. The data from these experiments will be analysed to determine the non-inferiority of Tdap vaccine in HIV-infected compared to HIV-uninfected women. We will investigate placental antibody transfer and wP antibody concentrations to demonstrate the effect of Tdap in pregnancy on infant wP responses. Finally, we will determine the correlation between Tdap antibody concentration and function in HIV-exposed and unexposed infants and their mothers. The results are of interest to industry, policy makers and regulators, all of whom have already been involved as stakeholders in the development of our proposal.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY
Title: Over two years: Does colonisation of the airways and sensitisation with Aspergillus fumigatus and other fungi contribute to asthma severity and treatment-resistance in children with severe asthma?
Funder: Action Medical Research

Abstract: Background Asthma affects approximately 1.1 million children in the UK and around 1 in 20 of those children has severe asthma which is uncontrolled despite high doses of corticosteroids. Frequent flare-ups, hospitalisations and steroid side-effects all lead to a poor quality of life and treatment options are limited. There is evidence to suggest that severe adult asthma starts in childhood. These researchers have found that round half of adults with severe asthma have fungi in their airways. These patients have worse lung function and respond poorly to bronchodilators. It is known from recent studies that certain components of fungi react with human proteins causing allergic lung inflammation. This has not yet been studied in children and it is possible that certain fungi may already be present in the lungs of children with asthma causing severe disease and eventually narrowing of the airways in adults after many years of persistent allergic lung inflammation. The research project This research aims to study the link between fungi in the airways and asthma severity in children. The researchers will measure chemicals in the blood of children with severe asthma that reflect an allergic reaction to certain components of fungi. They will see if children with high concentrations of these chemicals have worse lung function and more troublesome asthma than other children with severe asthma who do not have fungi in their airways. It is possible to treat fungal infections but treatments are expensive, need to be taken for a long time and carry a risk of side effects. Findings from this research will help doctors to decide which children with severe asthma are most likely to benefit from anti-fungal medication. These initial findings may also pave the way for a clinical trial.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Over two years for a molecular genetic analysis of primary ciliary dyskinesia in a high prevalence UK Asian population
Funder: Action Medical Research

Abstract: Background Primary ciliary dyskinesia (PCD) is a chronic genetic disorder affecting children from early life. The disease affects cilia, tiny hair-like appendages on the surface of cells that move fluids in the body. Cilia are particularly important in the lungs where they help to keep the airways free from germs and dust. Children with PCD face a lifetime of recurrent chest and ear infections and many other problems Their lungs can become permanently damaged, leading to surgery to remove part of their lung or even a lung transplant. In the UK over 3,000 people have PCD and over 100 children are diagnosed with the condition each year. Once their illness is correctly diagnosed, children can be given twice-daily physiotherapy, which helps clear their lungs. Many also take antibiotics on a regular basis to tackle infections. PCD is especially prevalent in the UK Asian population (affecting one in 2,300). However, as a result of relative isolation and reluctance to seek prompt medical attention, combined with misdiagnosis of this rare disorder, the disease can often be advanced when diagnosed. Early diagnosis and disease management are well known to be associated with better disease outcomes. The research project PCD is caused by at least 15 different genes and these researchers aim to use powerful techniques to define the genes causing PCD in at-risk UK-Asian families, initially in Bradford, Leeds and Luton. Characterising new PCD genes will improve our understanding of cilia functions and the molecular basis of PCD, paving the way towards future targeted gene-based therapies. The team will also work towards development of a gene panel ('Bradford chip') to enable rapid diagnostic screening. This, together with efforts to increase awareness of this rare disease, should speed up diagnosis. As knowledge of PCD genes expands, this benefit is likely to extend to the wider UK population. Early and appropriate treatment can relieve children's suffering, help stop their illness from getting worse and protect their lungs from permanent damage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Smart Combination Respiratory Medicines for Optimal & Cost Effective Patient Benefit
Funder: Innovate UK

Abstract: The Business-led APPS2B Project aims to identify, demonstrate, and quantify for the first time the mechanism for, and potential significant clinical benefits of hihghly innovative orally inhaled combination respiratory therapies, that have been optimally designed, engineered and manufactured for intent using Prosonix Multi-Component Particle (MCP) Technology.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Stem cell-based 3D tissue engineered organ for tracheal replacement
Funder: Innovate UK

Abstract: This project seeks to create a niche, highly defensible, innovative regenerative medicine product with a global commercial potential of an estimated minmimum £70M annually This is aimed at patients with a life-threatening disease which would otherwise be unattractive had the same team of experts not already tested a clinical prototype which has shown promise to be a one-off cure for severe structural airway disease. This project brings together these experts with other partners within a consortium to progress this clinically successful prototype into a commercially ready stem cell-based tissue-engineered trachea for the treatment of adults and children with life-threatening severe structural airway disease. We will deliver a clinical trial providing robust quality data, validated manufacturing processes and economic assessment to support an accelerated path to market for commercial exploitation in this indication and will open up market potential for similar organ replacement products in larger disease indications.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: Proving the feasibility of IKKe inhibitors as therapeutics for treatment of Chronic Obstructive Pulmonary Disease (COPD)
Funder: Innovate UK

Abstract: This project aims to establish the feasibility of a new treatment for Chronic Obstructive Pulmonary Disease – a highly debilitating condition that affects more than 200 million people worldwide and leads to over 6 million early deaths every year. The consequent social, economic, and health-care burden is huge. Treatment for COPD usually involves relieving the symptoms, for example by using drugs delived through an inhaler, or supplementary oxygen, to make breathing easier. However the novel therapeutic mechanism that will be pioneered by this programme will target the processes that cause the disease, which should significantly slow - or even halt - its progression. This key aspect differentiates this approach from that of existing drugs, and of many other experimental treatments.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: TRPA1 hit expansion and validation
Funder: Innovate UK

Abstract: Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are increasing within the global population. The UK has the highest prevalence of asthma in the world, with ~9 million people of all ages and race affected and where 90% of deaths are preventable. 3.2 Million people have COPD and ~23,000 people die from the disease each year, making COPD the UK’s fifth biggest killer disease. This increasing problem is recognised by the introduction of government guidelines recently set up to improve diagnosis and hence initiate earlier treatment of both diseases. However, current drugs are only able to treat the symptoms As the diseases progress and symptoms get more aggressive, these drugs simply do not provide adequate relief. It is our intention to find a new drug that is superior to the current treatments. Only when such a drug is available can we begin to see an increase in the quality of life to the people affected by these chronic diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY