NIHRDataInsights/HRCSData huggingface dataset:
Title: The responsiveness of anti-VEGF therapy and monocyte function in neovascular age-related macular degeneration
Funder: The Dunhill Medical Trust

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Neovascular AMD (nvAMD), which accounts for 90% of cases of AMD-related vision loss, is treated by the intravitreal injection of anti-vascular endothelial growth factor-A (VEGF-A) antibody. The therapy can stabilize disease progression and even improve vision. However, there is a huge variation on the responsiveness to the therapy, and about 1/3 of our patients do not respond to treatment. For those who respond well, some will develop macular geographic atrophic changes (i.e. dry-AMD). We believe that the variability in monocytes/macrophages angiogenic growth factor production may be related to the responsiveness of the patients to anti-VEGF-A therapy. In this study, we will examine monocyte angiogenic growth factor production in nvAMD patients and will correlate the data with their response to anti-VEGF therapy. The results will improve clinical practice on anti-VEGF therapy in nvAMD


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: EYE
Title: Prostaglandin F2-alpha eye drops in thyroid eye disease: a randomised controlled double blind crossover trial
Funder: Division for Social Care and Health Research (Wales)

Abstract: Thyroid eye disease (TED) is a chronic disfiguring and debilitating disease of the eyes which can lead to sight loss in severe cases. Patients with TED frequently have characteristic eyeball protrusion (proptosis) due to increased fat accumulation behind the eye. The discomfort and changes in appearance of the eyes is a source of severe psychological distress and impaired quality of life in many patients. Current treatments for TED are unsatisfactory and established non-surgical therapies which specifically reduce proptosis are lacking. Reduced eyelid protrusion has recently been reported as a side-effect of the use of prostaglandin analogue eye drops (e.g. Bimatoprost (PGF2-alpha)) in the routine treatment of glaucoma and we have laboratory data showing inhibition of fat cells by Bimatoprost. Hence PGF2-alpha eye drops potentially represent a simple, non-invasive low toxicity topical alternative to surgery in TED. However no clinical trials of Bimatoprost have been conducted in TED to date. The objective of this study is to determine whether bimatoprost eye drops are effective in reducing proptosis and thus improving quality of life in patients with TED. Trial participants will be recruited from the TED clinic at the University Hospital Wales. The clinic is a regional referral centre for the treatment and study of TED and is run by a multidisciplinary team of ophthalmologists, endocrinologists, and orthoptists with expertise in TED. Following informed consent, participants will be randomised to receive bimatoprost or placebo eye drops for three months after which they will undergo a two month drug washout period before switching to the opposite treatment in the final three months of study. The primary endpoint is a change in standardised measurements of proptosis while secondary endpoints will include changes in quality of life scores. This study will provide evidence for a novel application of bimatoprost in patients with TED.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE
Title: Laser photocoagulation for non-proliferative diabetic retinopathy
Funder: Department of Health (England)

Abstract: There are 2.5 million people diagnosed with diabetes in England 4200 people at risk of blindness and 1280 new cases of blindness caused by diabetic retinopathy every year. A key area of uncertainty for clinicians is whether to treat this condition with laser or the newer more expensive but possibly more effective therapies such as anti-vascular endothelial growth factors. This is an important topic for consumers because the consequence of treatment failure is blindness and both interventions involve considerable time and discomfort. A good quality systematic review is urgently needed to support the development of guidelines for treatment. The current version of the Royal College of Ophthalmologists Diabetic Retinopathy Guidelines is largely based on the narrative assessment of individual clinical trials. The current (unpublished) draft of the review includes 20 trials: recent searches indicate that there may be upwards of a further 40 reports to be considered for inclusion; search of www.clinicaltrials.gov identified 135 registrations of trials of diabetic retinopathy with laser intervention. The methods of the current review need to be substantially improved to include more rigorous assessment of the risk of bias in all included and new trials and to produce a summary of findings tables.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.3 MEDICAL DEVICES
Health categories: EYE
Title: Evaluation and development of a novel binocular treatment (I-BiT) system using video clips and interactive games to improve vision in children with amblyopia ('lazy eye').
Funder: Wellcome Trust

Abstract: Lazy eye (amblyopia) is caused by the presence of a turn in one eye or a focusing error resulting in a blurred image. The brain then ignores the eye in question. It is treated by wearing a patch on the good eye to force the use of the lazy eye: this is most effective in children up to age 8. The patch must be worn for hours each day for many months. Children dislike the patch as they cannot see properly whilst wearing it; it stops them using both eyes simultaneously; and it draws attention to them. We have developed instead a computerised system and game which allows the child to use both eyes simultaneously and only needs to be used for a short time each week. Early results indicate that this system is effective in treating lazy eye, and is greatly preferred by the children. Our proposal is to update the system using the latest technology, including the development of specialised games and videos for this treatment. Once the product is complete there will be two trials to determine how effective the treatment is, first compared with no treatment and then compared with conventional patching treatment.


Research activity codes: 6.3 MEDICAL DEVICES;5.3 MEDICAL DEVICES
Health categories: EYE
Title: Signal integration by annexin 2 during retinal phagocytosis.
Funder: Wellcome Trust

Abstract: In the eye, the light-sensing cells of the retina produce large amounts of new membrane every day. Once it has been used, the membrane is discarded to be engulfed as vesicles and disposed of by specialised neighbouring cells. This garbage disposal activity is vital, if it fails completely blindness rapidly ensues. We have discovered that a protein named annexin 2 is essential for the prompt clearance of the discarded membranes. The regulation of annexin 2 involves several distinct molecules, but it is not known whether these act in concert, or in sequence, or how their combined activities are coordinated. In this proposal we will address gaps in our knowledge concerning the function of annexin 2, and thus the vital cellular mechanisms that maintain a healthy retina. We will use mutants of annexin 2 designed to render the molecule insensitive to each of its regulatory influences, and by expressing these variants of annexin 2 in cultured cells and in the retinas of mutant rodents, we will generate new insight into how annexin 2 is controlled, and the downstream activities that it in turn controls.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE
Title: Melanopsin signalling: phototransduction, behavioural regulation and clinical relevance.
Funder: Wellcome Trust

Abstract: The eye performs two quite different light detecting tasks. Its familiar function is the collection of light to build a visual image of the world, whilst its less familiar role is to provide an overall measure of environmental brightness (irradiance) for the regulation of varied aspects of our physiology, including 24 hour sleep rhythms These very different forms of light detection seem to have driven the evolution of two classes of photoreceptor within the eye. The rods and cones for vision an d another, quite separate, group of photoreceptors based upon a small number of directly photosensitive retinal ganglion cells (pRGCs) which detect irradiance. Until recently, it seemed inconceivable that there could be an unrecognised class of photoreceptor within the eye, yet it was overlooked until the beginning of the 21st century. The aims of our research are to try and understand how this new photoreceptor system works, how it communicates with the brain and then how this light information is used by the brain to regulate physiology and behaviour. A key part of our research will be to translate what we know about the basic biology of these photoreceptors to improve the health and well-being of individuals with eye disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE
Title: Development of a synthetic biodegradable cell carrier membrane for the transplantation of cultured cells or freshly excised autologous tissue (limbalsegments or oral mucosa) for diseases of the cornea.
Funder: Wellcome Trust

Abstract: When the cornea is damaged by chemical or fire burns, vision is compromised. In cases where transplantation using a donor cornea will not work, it has become possible to use stem cell therapy to generate a functional corneal outer layer (epithelium). To do so, one isolates stem cells from the limbus that surrounds the cornea (from the outer eye or a donor) and cultivates them on an appropriate sheet or substrate to generate a transparent, stitchable and functional corneal epithelium. This is then transplanted on the patients's eye to offer significant restoration of vision. The material used currently to grow the stem cells on is the human amniotic membrane, obtained from maternity clinics. While this procedure has been successful, one would like to, if possible, replace the amniotic membrane, so as to avoid any viral contamination, shelf life degradation and other potential risks. It is here that a synthetic biodegradable polymer membrane developed by Sheffield University promises to be valuable. In this proposal, we aim to collaborate to develop and clinically evaluate the use of synthetic membrane as a replacement for human amniotic membrane. If successful, this will provide a safer, affordable, and more accessible alternative to the human amniotic membrane.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE
Title: The role of the apelin/APJ pathway in retinal vascular development and pathology.
Funder: Wellcome Trust

Abstract: The uncontrolled growth of new blood vessels and changes to existing blood vessels in the retina, the light sensitive part of the eye, is a major cause of blindness. These harmful changes occur in a number of different eye diseases but the most common is diabetes where loss of vision can affect up to 40% of patients. Although some advances have been made in the treatment of these conditions they still remain very difficult to control. There is therefore an urgent need to understand in much great er detail the biological mechanisms that cause these changes so that we can identify new targets for drug development. Our objective is to investigate the role of a newly discovered biological pathway, the apelin/APJ pathway, which our preliminary data has shown to be activated in abnormal retinal blood vessels. We will investigate in detail how this pathway contributes to the development of harmful blood vessels in the eye and gain insight into the biology so that we can identify potential ther apeutic targets. It is envisaged that this study will help us understand in more detail how blood vessel pathology in the retina occurs and how best to prevent this from happening.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Development and validation of a novel device for detailed visual field assessment.
Funder: Wellcome Trust

Abstract: Children and adults who suffer from certain types of brain tumours or other acquired brain or eye disorders can have visual problems resulting from defects in the their peripheral vision (visual field defects). In children these can only be very approximately measured in the clinic setting and similarly some adults have difficulties with the usual testing machine. We have developed a new system to detect visual field defects by monitoring a child's eye movements when he/she is sat in front of a TV screen. We wish to refine the test for different levels of brightness (threshold testing) and we wish to trial this new system in both children and adults. The system is patient friendly (child or adult), not at all threatening and does not involve any head or other restraints. All that is required is just a few minutes in front of a TV screen and this gives the doctor detailed information about the patient's visual field.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: EYE
Title: Investigation and manipulation of photoreceptor proteostasis.
Funder: Wellcome Trust

Abstract: Vision is our most precious sense. Vision begins with the detection of photons by specialized light sensitive photoreceptor cells at the back of the eye. The photoreceptor cells transform the light into an electrical signal that is then passed to the brain. Mutations in the light sensitive protein of photoreceptors, rhodopsin, are one of the most common causes of inherited blindness. The majority of rhodopsin mutations result in the faulty protein being produced. Mutations in other proteins also lead to faulty proteins that kill photoreceptors, such that this is a major cause of inherited blindness. This programme of research aims to understand the reasons why photoreceptors die when faulty proteins are produced. We believe that we may be able to use the natural cellular machinery for dealing with faulty proteins to counteract these negative effects and restore the natural protein balance within the photoreceptor (proteostasis). This understanding can then used to develop new therapies to help preserve vision.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Cell Biology and Pathology of the Retinal Pigment Epithelium
Funder: Wellcome Trust

Abstract: We wish to establish the fundamental molecular mechanisms underlying degradative and secretory pathways in retinal pigment epithelial cells (RPE) and understand the possible role of defects in these processes in aging and retinal disease. We established tools to analyse RPE membrane traffic pathways and accumulated evidence suggesting that defects in those pathways lead to premature aging and phenotypes associated with age-related macular degeneration (AMD). Here we propose to: i) identify the molecular mechanisms regulating degradation of phagocytosed photoreceptor outer segments and determine whether defects in phagocytic, autophagocytic or endocytic pathways in the RPE lead to intracellular deposits and lipofuscin accumulation characteristic of aging and retinal disease. ii) establish the molecular mechanisms underlying the secretory and degradative pathways regulating extracellular matrix turnover by the RPE and determine their contribution to the formation of extracellular basa l deposits that accumulate in aging and retinal disease. iii) characterise the molecular mechanisms regulating polarised secretion of chemo/cytokines and growth factors by the RPE and determine how their secretion is dysregulated in aging and disease. This comprehensive and ambitious programme will reinforce an established and fruitful collaboration between two complementary laboratories combining basic cell biological approaches and disease models, to provide new insights into disease mechan isms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE
Title: The epidemiology of glaucoma.
Funder: Wellcome Trust

Abstract: Glaucoma is a group of diseases in which damage occurs to the optic nerve. Itis a leading cause of blindness, both worldwide and in the UK. It is believedthat 8% of people in their 70's may suffer from glaucoma- roughly one person in 12. Blindness from glaucoma cannot be reversed by medication or surgery. From results of research into other diseases, it seems highly likely that specific changes in diet or increases in level of exercise may help to reduce the risk of developing glaucoma, or reduce the speed at which the disease progresses. However, very little scientific research has been done in this area. We aim to identify patterns of diet or lifestyle which increase the risk of glaucoma, and which may be simply and safely altered, reducing an individual's risk of blindness. This project therefore aims to inform and empower individual patients, allowing them to take more control of the care oftheir own health. This will involve analysing data that has been collected from participants in an existing study of the way diet and lifestyle influencerisk of disease.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: EYE
Title: Retinal repair using ESC-derived cone photoreceptor precursors.
Funder: Wellcome Trust

Abstract: Retinal degenerations leading to loss of photoreceptors are a major cause of untreatable blindness; in particular theloss of cone photoreceptors reduces visual acuity in patients. The Ali laboratory has previously demonstrated proof of principle for cone photoreceptor transplantation into the adult wildtype and degenerate retina. They have shown that cone photoreceptor transplantation is feasible provided the donor cell population are correctly staged post-mitotic coneprecursors, isolated at the peak of cone genesis. As far fewer cones are present in the murine retina compared to rod photoreceptors, a more appropriate strategy to generate cone photoreceptors for transplantation is the use of mouse ES cells. The recent publication of a 3D retinal differentiation protocol closely mimicking the developing neural retina not only provides a model system with which to test the specification of photoreceptors towards a cone cell fate, but also enables the generation of large numbers of photoreceptors for transplantation studies. We hypothesise, that detailed investigation of the developmental signals leading to the acquisition of cone photoreceptor cell fate will lead to improved generation of stem cell-derived cones. This cell population will present a potential to be transplanted to the degenerate retina in order to restore cone-mediated visual responses.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE
Title: Lineage analysis and functional studies in zebrafish retina.
Funder: Wellcome Trust

Abstract: Clonal analysis in the zebrafish retina has revealed that size and cellular composition of retinal progenitor clones is highly variable, leading to the question how this variability can ultimately lead to a highly organized tissue. Only recently, the Harris lab designed a model, showing that clonal size can be described by a stochastic process (He et al., 2012) rather than a deterministic developmental program (Livesey & Cepko, 2001). Following up from this stochastic model it is now time to ask how on a cellular basis those stochastic influences are implemented and which intra- or extracellular factors are mediating the switch between different proliferative phases, thereby guiding proliferation and


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE
Title: A phase I clinical trial of DARC
Funder: Wellcome Trust

Abstract: Detection of Apoptosing Retinal Cells (DARC) allows rapid and direct visualization of nerve cells dying in the retina through apoptosis, as occurs in Glaucoma, the major cause (15%) of irreversible blindness worldwide. Guide Dogs for the Blind Association UK reported recently that 10% earlier detection of Glaucoma would save £1billion/year in treatment costs alone. The novel DARC technology meets the unmet needs of Glaucoma diagnosis, namely methods allowing a) early disease detection (before permanent vision loss) and b) reliable testing of drug treatment efficacy. Our preclinical Glaucoma studies demonstrate DARC to have clear potential in these two areas, with immediate translational implications to patients. Early diagnosis through DARC will increase patient benefit and decrease burden of care costs. A Phase 1 Clinical Trial is needed to ensure the safety of DARC before its diagnostic benefits can be made widely available. The objective of this application is therefore to enable the undertaking of this trial to allow use of DARC in patients. Beyond the initial market of Glaucoma, recent experimental data supports the assertion that DARC can also be used to diagnose Alzheimer's and Diabetes. We envisage that this application will open the door to DARC being used as a primary healthcare diagnostic and screening tool eventually.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE
Title: Morphogenesis underlying choroid fissure fusion.
Funder: Wellcome Trust

Abstract: Coloboma is a defect in the morphogenesis of the eye that results from failureof choroid fissure closure. It is among the most common congenital defects in humans and can significantly impact vision. However, very little is known about the developmental mechanisms regulating choroid fissure fusion. Therefore, I aim to resolve the cellular and molecular mechanisms underlying choroid fissure closure by high-resolution 4D confocal imaging of zebrafish retinal cells during fusion. In particular, I will investigate how cell cycle progression regulates the epithelial remodelling that accompanies fusion.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EYE
Title: Clinical PhD Programme at the University of Edinburgh: "Rhodopsin trafficking defects in Retinitis Pigmentosa".
Funder: Wellcome Trust

Abstract: Retinitis Pigmentosa (RP) is an inherited disease of the back of the eye (retina) affecting 1 in 3000 people in the UK. It causes visual loss in young adults which can progress to blindness by the time a patient is 40 years old. At present there is no treatment for RP. Recent advances in gene therapy have opened up the possibility that it could be used as a treatment for RP. However much more laboratory work is required before this option can be realised. At present there is no ideal way to examine the effect of gene therapy on RP. However, with recent advances in stem cell technology it is now possible to grow cells in a lab which resembles the retina. My research aims to grow retinal cultures from stem cells of patients with RP.I will then use these cultures to better understand the disease. I will then determine whether gene therapies, which have been produced to treat RP, have a positive effect on the cultures I have grown. This will help move towards a first ever treatment for RP.


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