NIHRDataInsights/HRCSData huggingface dataset:
Title: Adhesion to host cell membrane microdomains in cornea as an antimicrobial target to prevent corneal ulceration
Funder: Medical Research Council

Abstract: Clinicians at the LVPrasad Eye Institute identified a vital need for effective first line therapy for patients in rural India with early stage eye infections. Without appropriate treatment, infections can quickly progress into irreversible corneal ulceration with loss of sight. LVPEI alone see 1200 cases of corneal infection per year: 30% will experience vision loss. In LMIC, many eye infections result in corneal ulceration and 10,000 patients per year lose eyes that might otherwise be saved Inhibiting the adhesion of bacteria to the cornea is an innovative, low-risk strategy to prevent ulceration. Pathogens use a variety of means to adhere but all are dependent on interactions with molecules on the host cell surface. These are frequently located within highly organised microdomains, allowing control of the strength of adhesive interactions, allowing them to resist mechanical removal by mechanisms such as tear production and blinking. Human tetraspanin family proteins form microdomains that organise adhesion receptors such as integrins. Several species of pathogens use these microdomains for tight attachment to host cells. Treatment with tetraspanin-derived peptides weakens the attachment of a range of microbes and facilitates removal by natural defences. Importantly, an interaction occurs between the peptides and antibiotics that will allow the continued use of common antibiotics. We aim to apply this treatment to microbial keratitis in India, exploring the effect of the peptides on common infections and the underlying mechanism, to promote the development of a safe and inexpensive topical treatment. The targeting of a broad range of pathogens allows treatment without diagnosis. This will benefit economically active people who damage their eyes during agricultural or domestic labour. Loss of sight from eye infection exists in other LMIC and our treatment will be appropriate for corneal infections in other areas lacking an integrated healthcare system.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: EYE
Title: Understanding the molecular and cellular complexity of human cornea through single cell analyses
Funder: Medical Research Council

Abstract: Cornea is the transparent front part of the eye which together with the lens focuses the light onto retina for visual processing. Corneal blindness is the 2nd main cause of blindness worldwide accounting for 23 million patients. In Europe, over 40,000 blind people are waiting for corneal transplant every year. Despite efforts to develop corneal substitutes to alleviate both the shortage and the drawbacks of human donor tissues, surgery with allogeneic epithelial donor tissue has remained the gold standard; however this does not work for corneal diseases caused by the dysfunction of stroma or endothelium. Developments in bioengineered corneal substitutes designed to replace diseased corneas have been reported; however their clinical use has been limited due to multiple challenges including lack of integration into the surrounding tissue, complex implantation procedures and serious complications. Clearly, there is an unmet need for the design of new smart biomaterials and stem cell therapies to create corneal structures that are indistinguishable from the original native tissue and fulfill the natural functions of the cornea. By understanding the physical and cellular structure of the tissue and the resulting impact of the structure on biological function, novel materials for a number of ophthalmic clinical applications can be designed. Furthermore, by extending this structure-function approach to characterizing corneal disease processes, new therapies can be engineered. This application aims to utilize the most recent advances in single cell sequencing to reveal the intricacies of corneal structure at the cellular and molecular level from early development to adulthood. Data generated from this project will be deposited into Data Coordination Platform contributing to the Human Cell Atlas and providing the scientific and clinical community with comprehensive datasets that can be further mined and exploited in the context of normal development and corneal disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: scEye-Map: Developmental trajectories of progenitor cell populations in the human eye at single cell resolution
Funder: Medical Research Council

Abstract: Cell types within the adult eye have been extensively studied and categorised. Single cell transcriptomic of the adult retina has been used to define novel cell types (e.g. macroglia) and confirm that these have progenitor-like cell characteristics. From cell culture experiment there is also evidence for multiple progenitor-like cells within the iris and ciliary apparatus in particular but the molecular markers for most of these cells are not yet available. The cell populations within the embryonic human eye are much less well defined and the developmental trajectories of the different populations across developmental time are largely unknown. We have access to early embryonic material via HDBR and to adult eye tissue via the Moorfields tissue bank. We propose to use single cell technologies to map all of the major cell populations within the embryonic eye across critical periods of morphogenesis/early retinal development and compartments of the adult eye known to be enriched in progenitor-like cells. The main aims of this project are to help understand major developmental disorders affecting the eyes and identify cell populations within the adult eye that have regenerative potential.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Role of Avastin in trabeculectomy surgery
Funder: Moorfields Eye Charity

Abstract: Pharmacology enhancement of trabeculectomy (glaucoma filtration) surgery using 5-flurouracil 95-FU) and mitomycin-C (MMC) has significantly improved success rates. However the non-specific mechanism of action of these agents, especially MMC, can result in widespread cell death and avascular blebs that are susceptible to leakage and infection. More predictable modulators of wound healing are required. Tenon’s fibroblasts cells are the main effector cells in the initiation and mediation of wound healing (scar tissue formation) after trabeculectomy surgery. Excessive wound healing results in unwanted high eye pressure after trabeculectomy surgery. Vascular endothelial growth factor’s (VEGF) plays a pivotal role in wound healing, as it mediates the signal transduction cascade leading to tenon’s fibroblast migration and proliferation, as well as collagen gel contraction. This is the process of scar tissue formation. Reports using bevacizumab (Avastin), and anti-VEGF agent as an adjunct for trabeculectomy suggest a promising role in modifying the wound healing response. However, its effect as a solitary agent may be insufficient. A recent rabbit study reported that combined subconjunctival injections of 5-FU and bevacizumab may have an additive effect on bleb survival with improved morphology. We propose a pilot study to assess the safety profile and efficacy of this combination in humans and compare against current standard practice of trabeculectomy augmented with MMC. The pilot will randomised 30 patients to receive either standard trabeculectomy with MME or standard trabeculectomy with serial subconjunctival Avastin + 5-FU injections. Follow-up will be for 18 months.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE
Title: Eye2Gene: assisting genetic diagnosis of inherited eye disease with artificial intelligence
Funder: Moorfields Eye Charity

Abstract: Medical imaging and genomics are two biotechnologies which are revolutionising medicine and in particular ophthalmology. Combining these two powerful approaches and integrating and analysing the vast amounts of data using computers will improve the accuracy of our genetic diagnosis and we hope help in the future to lead to new discoveries.This project will utilise the latest technologies and skills in computer science to make sense of data using Artificial Intelligence. Work by Dr Pontikos will aim to apply machine learning so that retinal images and genetic data can help clinicians and scientists understand and potentially apply a diagnosis with the help of Artificial Intelligence. He will collect significant amounts of data from the project which will be analysed and shared with collaborators at the UCL Institute of Ophthalmology.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: EYE
Title: Cenegermin for treating neurotrophic keratitis [ID946]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of cenegermin within its marketing authorisation for treating neurotrophic keratitis.

Lay abstract: Neurotrophic keratitis is a degenerative condition which affects the cornea (the clear layer covering the front of the eye). Damage to the nerve connected to the cornea causes a loss of sensation and impairment of healing, which leads to breakdown of the epithelium, ulceration and perforation. The most common causes of neurotrophic keratitis include viral infection (in particular, herpes), intracranial lesions (such as tumours or aneurysms) and injuries to the eye or nerves (for example, surgery, chemical or physical burns, or drug toxicity). It can also be caused by systemic diseases such as diabetes and multiple sclerosis. Neurotrophic keratitis can be classified into 3 stages, based on the severity of corneal damage. Stage 1 (mild) disease is characterised by mild, non-specific symptoms and changes to the corneal epithelium, whereas in stage 2 disease (moderate) the damage to the cornea is persistent and does not heal. Stage 3 (severe) neurotrophic keratitis is characterised by corneal ulcer, perforation and stromal melting. Neurotrophic keratitis is a rare condition. The prevalence is estimated to be between 1.6 per 10,000 people (based on the prevalence of keratitis after herpes infection and after surgery for trigeminal neuralgia)(1) and 4.2 per 10,000,(2) of whom about one-third have stage 2 or 3 disease. This implies there may be fewer than 17,708 adults with neurotrophic keratitis in England,(3) although the precise number is unknown. Management of neurotrophic keratitis aims to promote healing of the epithelium and prevent progression of corneal damage, and is based on the clinical stage of the disease. Management of early-stage disease focuses on addressing any underlying causes. For stages 2 and 3, options include therapeutic contact lenses, closure of the eyelid, collagenase inhibitors (for stromal melting) and surgery (for example, amniotic membrane transplant and conjunctival flap surgery). Preservative free artificial tears may be used at all stages of the condition. Management should consider the underlying cause of the neurotrophic keratitis, in particular whether it is related to an ongoing progressive condition (such as diabetes or multiple sclerosis) or an acute or non-progressive cause (such as surgery or an injury). References: 1.Sacchetti M and Lambiase A (2014) Diagnosis and management of neurotrophic keratitis. Clinical Ophthalmology 8:571–9. 2. European Commission (2016) Orphan drug designation (EU/3/15/1586) for recombinant human nerve growth factor for the treatment of neurotrophic keratitis. Accessed September 2017. 3. Office for National Statistics (2017) Population estimates for UK, England and Wales, Scotland and Northern Ireland, mid-2016. Accessed September 2017.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE
Title: Cross-Institutional Collaborative Themes and Training
Funder: Department of Health and Social Care

Abstract: Our overarching aim is to provide the premier environment for training and the delivery of translational ophthalmic research, by growing and empowering an integrated community of diverse experts to address rapidly, effectively and efficiently, the challenges of eye disease and associated disorders. Our new cross-institutional research cluster structure (spanning IO and MEH, and linking with UCL, UCLP Academic Health Science Centres (AHSC) and other sectors) is the vehicle for this. It also enables us to offer a comprehensive range of training opportunities for discovery and clinical scientists at all stages of career and from many disciplines, including new methodologies like stem and gene therapy and big data usage. Short-term goals: 1) Align major research goals through cluster groupings and BRC infrastructure, with large-scale funding opportunities (including philanthropy and industry); 2) Expand our educational portfolio and strategy, and initiate new delivery of educational packages. Our mission is to provide education and training across the breadth of needs for enhanced eye research Medium-term goals: 1) Major increase in large-scale multidisciplinary research programmes with external income up > 50%; 2) An established portfolio of inter-related education and training opportunities for the needs of the next decade, with 30% more uptake on our courses/programmes. Long-term goals: 1) A sustainable, world-leading, multi-disciplinary workforce meeting the next generation’s eye research needs; 2) Delivery of a new purpose-built facility for eye care, research and training within 7-10 years; 3) Continuing recognition as the ‘go to’ site globally for diverse education and training opportunities in ophthalmology, particularly research.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: EYE
Title: A study of the first transgenic mouse model of Infantile Nystagmus
Funder: Wessex Medical Research

Abstract: Nystagmus is an uncontrolled, to-and-fro oscillation of the eyes, which occurs in 1 in 1500 infants and is associated with poor vision. The student will exploit the opportunity to establish a relevant model for future treatment studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: INSIGHT: The Health Data Research Hub for Eye Health
Funder: Medical Research Council

Abstract: "T he INSIGHT Digital Innovation Hub (INSIGHT-DIH) focuses on Eye Disease and ‘Oculomics’ , a first-of-its-kind linkage of routinely collected, anonymised high-dimensional eye-imaging data from the major ocular diseases impacting blindness to wider health including diabetes, dementia, cardiovascular disease and inflammation/immunity . INSIGHT-DIH partners NHS (University Hospitals Birmingham NHSFT, Moorfields Eye Hospital NHSFT), charities (Action Against Age-related Macular Degeneration) and industry (Roche, Google), to enable innovation and transform patient care. Eye/vision problems affect 1.3 billion people worldwide but is highly amenable to digital innovation. In particular, ocular imaging can be used to provide novel insight into both eye and systemic health (“oculomics”), from childhood to old age. The INSIGHT-DIH network gathers data from across the whole of the UK health sector - NHS clinics, imaging diagnostics, laboratories, primary care/optometry – which will be linked and anonymised within the DIH to build the first holistic data-record combining routine systemic and eye health data with unparalleled high-order retinal imaging centred on patient benefit. This positions the INSIGHT-DIH as an ideal exemplar for making the NHS ‘AI-ready’ . Eyecare data is standardised, large-scale (10% of all NHS appointments; >25 million scans/yr), and with proven suitability for artificial intelligence (AI) health applications (e.g. automated retinal diagnosis). INSIGHT-DIH will support innovation, making existing inaccessible datasets discoverable , and bringing scale and efficiency to dataset aggregation and curation of anonymised routinely collected data , utilising our existing UK network. We will address the ‘implementation gap’, with NHS partners being accelerated in digital maturity to AI-ready work-flows. Disease-focused image-linked datasets respond to NHS/industry needs and DIH priorities: (1) diabetes and diabetic eye disease; (2) age-related macular degeneration ; (3) dementia; (4) community cohort for AI-intervention development/evaluation to improve screening and access to care. Datasets will be scaled towards national coverage. Additional services include: rapid-response real world evidence (RWE); ‘smart clinical trial’ capability for pharmacological/device/AI-interventions; and ‘clinical/technical Faculties’ of domain experts. INSIGHT-DIH is underpinned by public trust and co-development, with a further £1 million investment in public and patient involvement and engagement (PPIE) as part of this bid, and creation of a Data Trust (Open Data Institute; AAAMD). From first contact to project completion, we will ensure excellence in service, with a view to sustainable partnerships, value return to all parties and a transformation in patient care."


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: EYE
Title: First in human phase I / II clinical trial of RAFT for aniridia related keratopathy.
Funder: Medical Research Council

Abstract: Aniridia is an orphan heritable disease (1:100,000 incidence) in which PAX6 gene mutations cause severe blinding developmental eye problems. Aniridia-related keratopathy (ARK) manifests as persistent, chronically painful defects of the outer epithelial layer of the cornea, vascularisation and scarring. This correlates with dysfunction in the ability of limbal epithelial stem cells (LESC), stromal cells and matrix to maintain normal corneal epithelium. ARK induced light sensitivity can lead to social exclusion. Current treatments include whole tissue transplantation and cultured LESC therapy which have both shown poor long-term outcomes. This may in part be due to 1) antigen presenting cell presence in whole tissue transplantation and 2) stromal cell absence in cultured LESC therapy. An optimal ARK treatment would include transplantation of both healthy LESC and a stroma populated with stromal cells. Our proposed solution utilises our patented technology known as RAFT (Real Architecture for 3D Tissues) in which LESC and stromal cells are co-cultured in a transplantable type I collagen-based tissue equivalent. Good manufacturing practise (GMP) protocols have been established in our pre-GMP laboratories and RAFT has undergone pre-clinical safety studies in a rabbit model. Having obtained regulatory advice (MHRA) we now need to undertake 1) GMP protocol validation in our Cells for Sight MHRA/HTA licensed manufacturing facility, 2) finalise IMPD to submit for clinical trial authorisation of a FIH transplantation study and 3) proceed to first in human RAFT transplantation studies in patients with ARK. In this phase I/II clinical trial we will perform RAFT transplantation in one eye of 21 systemically immunosuppressed ARK patients to assess RAFT safety and preliminary efficacy. The outcome measures will include corneal surface normalisation and stability (lack of conjunctivalisation, vascularisation and epithelial defects, and improvement in corneal clarity).


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: EYE
Title: Modelling the corneal microbiome to improve identification of pathogenic microorganisms
Funder: Medical Research Council

Abstract: Microbial keratitis (MK) is a major cause of blindness. The likely causative microorganism is only isolated in 40% of cases using conventional diagnostic culture (CDC). More sensitive methods such as microorganism targeted polymerase chain reaction (MTPCR) and next-generation sequencing (NGS) increase the detection of microorganisms but may increase the likelihood of picking up commensal microorganisms. A novel, minimally invasive corneal sampling method using a corneal impression membrane (CIM) enables sampling of both affected and unaffected eyes. The primary aim of this fellowship is to better define the identification of pathogenic microorganisms in patients with MK through a better understanding of the corneal microbiome in health and disease. I will develop an ex-vivo porcine corneal infection model to determine the sensitivity and specificity of CDC and MTPCR for different bacterial species at different stages of infection. Simultaneously, I will run a clinical study at St Paul's Eye Unit, recruiting 151 MK participants and 80 participants to 4 control groups. CIMs and swabs will be obtained from the cornea, conjunctiva and eyelids of MK participants affected and unaffected eyes, in addition to nasal swabs. Control participants will have all samples obtained from one eye. All samples will be processed using CDC and a subset using MTPCR and NGS. A comparison of identified bacteria obtained from CDC, MTPCR and NGS processing will be made. Microorganisms identified in the eyes with MK will be compared to the control fellow eye and other control groups and subtractive bioinformatic methodology applied to identify the likely pathogenic organism. Comparisons will be made between the microorganisms isolated from the cornea and contiguous sources to identify any possible endogenous sources of infection. This will facilitate potential future use of NGS in routine ophthalmic clinical practice, leading the way for personalised diagnosis and treatment of MK.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: EYE
Title: SWISH (See Well to Stay In ScHool: Randomised trial of spectacle distribution to decrease secondary school dropout rates in rural communities)
Funder: Medical Research Council

Abstract: Research question: Will providing free glasses to myopic rural Chinese students, with a teacher incentive to promote use, increase high school attendance? Design: Cluster-randomised controlled trial Rationale: Rural Chinese children have high myopia prevalence, but poor access to glasses. Our previous trials show giving free glasses significantly improves academic performance, with greater effect size than parental education or family income, equaling or exceeding other classroom-based medical interventions. Non-vocational high school attendance is only 30% in rural western China. Strong evidence of educational benefit from glasses is needed to spur adoption of national distribution programs. Methods: Children in Year 1 and 2 (1 class each) at 130 randomly-selected middle schools in Ningxia, western China, will be randomized by school to receive free glasses and a trial-proven teacher-based incentive to promote wear (Intervention) or prescriptions only (Control). The main outcome 2-3 years later will be high school attendance (powered to detect 10% increase); secondary outcomes of compliance, test scores and use of near versus distance classroom learning aids will elucidate biological plausibility of a causal pathway between myopia correction and learning. Local knowledge and attitudes about myopia and spectacle use and intervention cost-effectiveness will be studied. Team: PI Congdon, a public health ophthalmologist, is fluent in Chinese and has appointments at the UK (Queen's) and Chinese (Zhongshan) applicant institutions. The Queen's team includes a trialist, Chinese-speaking statistician, health economist and medical anthropologist. Chinese collaborating institutions are Zhongshan, China's leading eye hospital, and Shaanxi Normal, with close ties to Ningxia education authorities. Trial partners include Stanford REAP, a leader in impact evaluation in Chinese schools. This team has conducted multiple trials on glasses and learning in China.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: EYE