NIHRDataInsights/HRCSData huggingface dataset:
Title: Retinal repair using embryonic stem cell-derived cone photoreceptors
Funder: Medical Research Council

Abstract: Aim: To determine if sight loss caused by degeneration of the retina can be restored by transplantation of cone photoreceptor cells derived from embryonic stem cells. Background: Degeneration of the light-sensitive photoreceptor cells (rods and cones) accounts for the majority of people with untreatable blindness. Photoreceptor cells that are lost or damaged cannot regenerate, and the associated sight loss is currently irreversible. However, restoration of sight to people with retinal degeneration might be achieved by transplantation of photoreceptor cells from healthy donors. Previous work in the Ali laboratory has demonstrated that rod-mediated (dark-adapted) sight can be restored by transplantation of rod photoreceptors from a healthy donor when the transplanted cells are at a specific age of development. More recent work in the lab has shown that transplantation of cone photoreceptors, which are critical for normal sight in light-adapted conditions, is also possible. However, transplantation of cone photoreceptors is much less efficient than that of rods, possibly because only a relatively small minority of cone cells are obtained from the donor. Research Plan: I propose to expand the number of cone photoreceptor available for transplantation by promoting development of cone cells in 3-dimensional laboratory culture from embryonic stem cells. I will use complementary approaches to manipulate signals that are both extrinsic and intrinsic to developing photoreceptor cells. To find out if the efficiency of cone transplantation is limited by the concomitant delivery of rods, I will enrich the donor population for cones by cell sorting. Once sufficient cone photoreceptor development has been achieved in the laboratory, I will transplant this cell population into the adult healthy retina and those with retinal disease. Given that cones constitute only a minority of photoreceptors, valuable function might be restored with the replacement of relatively few cells.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE
Title: Enhancing outcomes in minimally invasive corneal endothelial transplantation
Funder: Medical Research Council

Abstract: In this fellowship I will investigate the parameters required to reliably produce 'Lock & Key' DMEK-S (Descemets membrane endothelial keratoplasty) grafts. We hypothesize that optical (OCT) coherence tomography could be used for precise guidance of of the femtosecond laser for laser dissection of the graft and host corneas which will standardize the process. We also hypothesize that reduced manual donor tissue manipulation and enhanced organ culture media can limit iatrogenic endothelial cell loss and improve storage time pre-transplant. Preliminary work will be carried out on human corneoscleral rims (normally discarded after transplantation) or donor tissue that is unsuitable for transplantation. Transplant grade corneas will only be required during the final stages of this research if the techniques are shown to be viable and a patient study is undertaken. The objectives are: 1) Defining the parameters required for consistent DMEK-S preparation using image guidance 2) Examination of graft smoothness, shape memory and adhesion properties of DMEK-S donors using atomic force microscopy 3) To determine endothelial cell viability before and after cutting, and the effect of returning pre-cut grafts to storage media 4) To investigate whether the addition of culture supplements and/or the ROCK inhibitor Y-27632 can limit iatrogenic cellular loss and enhance graft storage times. By identifying the necessary strategies required to produce and store 'Lock & Key' DMEK-S grafts we aim to widen the access to enhanced endothelial keratoplasty techniques and disseminate the benefits to patients. By performing this work in an eye bank setting from the outset we hope our work will ready to translate into improvements for patients within a short timescale. Although the trial will be extrinsic to this project, if progress is good, we hope to proceed to a phase 1 clinical trial of Lock & Key DMEK-S in year 3.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: A flow cytometry facility for ocular regenerative medicine
Funder: Medical Research Council

Abstract: We have a world leading regenerative medicine programme that covers photoreceptor, RPE, Muller cell and corneal limbal cell transplantation. As well as producing paradigm-shifting pre-clinical research (e.g. MacLaren et al., Nature, 2006; Pearson et al, Nature 2012), we have established some of the world's first clinical trials involving limbal stem cells and human ES -derived cells. Currently we have over £16M in funding, including over £6M from MRC/TSB/BBSRC. In order to maintain our world leading cell transplantation programmes, we now require a dedicated flow cytometry facility that would greatly improve our ability to refine cell populations for transplantation. It is essential that these facilities are housed within the Institute to ensure that freshly obtained biological material is rapidly processed. We are requesting funding for a state-of-the-art FACS sorter (BD Influx 5L manufactured by Beckton Dickinson - cost £413, 540) and a FACS analyser (BD Fortessa5L, manufactured by Beckton Dickinson - cost £216,075). These will allow 6-way sorting and up to 18-colour analysis. We are also requesting £45,000 for laboratory alterations (a partition, changes to benching, air conditioning, electrical supplies and fitting of blackouts) in order to house the equipment. We have secured over £427,000 from UCL and the Special Trustees of Moorfields Eye Hospital to support this facility. This includes salary support for a Grade 8 position for 5 years and £20,000 per annum towards service costs over the same period. UCL will contribute £150,000 and The Special Trustees will contribute £277,000. Services charges (at a similar rate to other cytometry facilities) will allow us to build a fund to support the running costs of the service beyond the 5 years provided by UCL and Special Trustees. Extrapolating from our current usage of external facilities we conservatively anticipate being able to recover at at least £50,000 of running costs per year.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE
Title: Evaluation of Mechanism to Prevent Posterior Capsular Opacification (PCO) in Paediatric Cataract Surgery
Funder: Medical Research Council

Abstract: Paediatric Posterior Cataract Opacification (PPCO) remains the most common complication of pediatric cataract surgery and occurs in almost every operation. It is caused by rapid and aggressive proliferation and migration of residual Lens Epithelial Cells (LECs) left in the capsule bag after cataract surgery. Theoretically, since these residual cells are responsible for the opacification, their removal at the time of surgery should reduce or remove the risk of aggressive proliferation of cells and PPCO. A simple cell removal procedure has been developed by use of hyperosmolar irrigation solutions that cause cell shrinkage and detachment from the lens capsule bag. However, this procedure must overcome cellular Regulatory Volume Increase (RVI) defense mechanisms that protect against shrinkage. We have previously shown that the RVI mechanism in LECs can be selectively disabled by using a combination of hyperosmolar shock and inhibitors of the Na/K/2Cl cotransporters. Thus selective shrinkage and detachment would completely remove LECs as a potential treatment for the prevention of PPCO. Preliminary results have been extremely promising and we are therefore ready to move to the next stage of full animal trials to assess long-term in vivo efficacy and chronic adverse effects (if any) of the treatment protocol, and to optimize some key parameters to a level suitable for clinical implementation. More specifically we need: 1. To conduct a full rabbit trial to assess long-term in vivo efficacy and chronic adverse effects (if any) of the therapy. 2. To refine the treatment procedure to a level suitable for clinical trials, for example, to shorten the treatment duration, develop a suitable application technique to introduce the therapeutic solution into capsular bag and to confirm the impact of a cell-free-capsule on its elasticity and clarity.


Research activity codes: 5.4 SURGERY
Health categories: EYE
Title: Exploitation of an ex-vivo disease model to characterise early events in retinal degeneration
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Age-related Macular Degeneration (AMD) is a degenerative disease of a critical region of the retina known as the macula. AMD affects 50 million people globally and poses increasing risks from midlife onwards, resulting in the irreversible loss of central vision. A key process in AMD is the gradual impairment of the Retinal Pigment Epithelium (RPE), a monolayer of cells in the retina which maintains photoreceptors as well as the blood-retinal barrier. Early AMD is asymptomatic, but typified by the presence of sub-RPE deposits known as drusen, associated with local inflammation. Loss of central vision in late AMD is correlated with RPE/photoreceptor atrophy and proliferation of new vessels through the blood-retinal barrier. Although some treatment is available, the majority of patients eventually lose their central vision. AMD is a complex disease, where underlying processes are incompletely understood, particularly during early stages. To address this, numerous experimental models of AMD have been created in rodents, rabbits, pigs and primates. However, no single animal model has reproduced the full disease spectrum, while the widely utilised rodent models suffer from the absence of a macula, the key structure damaged in the human eye. The recent discovery that Abeta, a remarkably penetrative and highly toxic protein is involved in key stages of retinal pathology has opened up new possibilities in elucidating early mechanisms driving RPE impairment. Here we aim to replace, reduce and refine the number of animals used in early AMD studies by exploiting an ex-vivo culture model of AMD which reproduces salient features of early disease including drusen formation and inflammation. This model will be used to elucidate the role of Abeta and inflammation in early RPE dysfunction. We are supported by KalVista Pharmaceuticals, an industry leader in the design/development of anti-inflammatory inhibitors, providing translational capacity to any findings from this work.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Developing Molecular Therapies for Glaucoma using an Ex-Vivo Human Organ Culture System
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Primary open angle glaucoma is a major cause of visual morbidity affecting more than 60 million individuals worldwide; and the second most common cause of blindness in the world: resulting in bilateral blindness in 4.5 million people. Elevated intraocular pressure (IOP) is a major risk factor for developing glaucoma. Animal models have formed an integral part of research into glaucoma pathogenesis, and to determine the efficacy of therapeutic interventions to control intra-ocular pressure. The most representative non-human glaucoma models are primates but there are a number of ethical and economic reasons which make this a difficult model for most glaucoma research groups to utilise. The principal aim of this studentship is to establish an ex-vivo human organ culture system glaucoma model and to use this model to evaluate the therapeutic potential of manipulating transforming growth factor-β (TGF-β) signalling in glaucoma.This disease model recapitulates the disease phenotype in the human eye and downstream experiments are performed in human tissue. Glaucoma pathogenesis involves increased aqueous humor outflow resistance, a result of several morphologic and biochemical changes in the trabecular meshwork. This project aims to evaluate the potential of TGF-β blocking peptides and siRNAs in the management of IOP as a therapeutic intervention for glaucoma. The human organ culture system glaucoma model recapitualtes the in-vivo human disease. It is anticipated that this project will lead to the wider adoption of this glaucoma model by other research groups in both academia and industry which would significantly broaden the impact of this project and represent a significant further replacement or reduction in animal use within the wider research community.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: EYE
Title: Generating zebrafish models of human eye movement disorders to replace mouse models
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The major aim of our proposal is to generate zebrafish models of a human eye movement disorder, to replace mouse models. Eye movement disorders affect 1% of the human population. In severe cases, such disorders can result in amblyopia and partial blindness, and there is currently no effective treatment. Duane Retraction Syndrome (drS) is a congenital form of squint in which horizontal eye movements are defective. Patients with drS have abnormal wiring of the ocular motor system - the nerves and muscles that control eye movements. We previously showed that drS can result from mutations in the cytoplasmic signalling molecule alpha2-chimaerin, and demonstrated that transient manipulations of alpha2-chimaerin signalling in the chick and zebrafish model systems leads to defects in ocular motor wiring, akin to drS in humans. In this proposal, we will make more permanent models of drS, to act as a resource for the research community. We will generate stable transgenic zebrafish lines with loss- or gain-of-function of alpha2-chimaerin, in order to determine the effects of chimaerin signalling levels and to model drS. Gain-of-function models will either over-express the wild-type alpha2-chimaerin protein, or will harbour human alpha2-chimaerin mutations. We will map the neuroanatomy of the ocular motor system in these lines, and functionally test the optokinetic reflex to determine the impairment of eye movements. These data will be directly compared with neuroimaging and functional data in humans, to gain insight into the causation of drS. Our zebrafish models will be disseminated to the research community, as a replacement and a desirable alternative to the mouse. All experimental analysis will be carried out on larvae at 1-5 days post-fertilisation, and therefore not 'protected' species. Neuroanatomical studies will involve live and time-lapse imaging allowing quantitation of multiple parameters from a single animal, thus allowing a reduction of animal usage.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE
Title: Prevent blinding retinal diseases by developing effective new treatments including gene and cell therapies.
Funder: Department of Health (England)

Abstract: The majority of people with sight impairment are affected by disorders of the retina, which is the layer of light-sensitive nerves in the eye. Prof. Bainbridge aims to develop effective new treatments, including gene therapy and cell transplantation surgery.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.4 SURGERY
Health categories: EYE
Title: Development of a visual fields test for children using interaction with both computer software and electronics hardware that combines to simulate an engaging and enjoyable game experience.
Funder: Department of Health (England)

Abstract: Knowledge of a patient’s visual field provides precious information towards the management of many ophthalmic and neurological conditions. When measured correctly visual fields can be powerful tools to help diagnose and monitor conditions such as glaucoma and nerve tumours as well as being important indicators of a person’s functional abilities. However measuring visual fields can be difficult - most methods require the subject to keep their eyes fixated on one central spot and reliably respond to stimuli in the periphery of their vision, without losing the central fixation. This is often prohibitively difficult for younger children, with their limited attention spans and poor compliance with instructions. We have already developed novel interactive computer software and physical toy structures designed to maintain children’s attention and compliance whilst simultaneously performing visual fields assessment.1 We will enhance this game-based visual fields tester based upon experience from the feasibility studies and feedback from the public including both children and parents. We will upgrade computer monitor and software to the highest professional standards. We will upgrade other physical structures and electronics components to ensure they perform more reliably and are more attractive to look at for children, in keeping with the philosophy that children should regard this as an entertaining and enjoyable experience. We will generate a database of normal results and use this information to inform programming of a final discriminating fields analysis system. We will establish the discriminatory power (sensitivity and specificity) of this final system with control and patient sample populations. The patient sample will include children with established clinically significant field loss. Finally, we will repeat the test on a sub population to establish the test-retest variability. We aim within the period of this research to produce an optimised game-based visual fields test for children with demonstrated sensitivity, specificity and reliability, that is also acceptable and enjoyable for children to use.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE
Title: Personalising Patching for Amblyopia Treatment
Funder: Department of Health (England)

Abstract: Background Amblyopia is a developmental disorder of human spatial vision in which a deficit of resolution cannot immediately be alleviated by refractive correction in an otherwise healthy eye. It is the commonest visual disorder of childhood in the Western world, (prevalence approximately 2-5%) [1] and accounts for 9 out of 10 appointments to the NHS Children’s Eye Service. [2] Mainstay treatment of amblyopia is refractive correction with spectacles followed by degradation of spatial input to the dominant eye by occlusion, predominantly patching. Currently, occlusion tends to be prescribed on an ad hoc basis ranging from 30 minutes daily to all waking hours and continuing for months, often years. Treatment is very demanding for the child and their family and outcomes are often very disappointing. Aims To use data previously obtained from two clinical trials (monitored occlusion treatment for amblyopia study [MOTAS] and randomised occlusion treatment for amblyopia study [ROTAS]) to explore and develop experimental treatment regimen(s) incorporating key patient characteristics: a 'personalised dosing strategy' (PDS) for the treatment of childhood amblyopia. To conduct a randomised controlled trial comparing two occlusion patching strategies: 'personalised dosing strategy' (PDS) derived from the above modelling exercise with a standard treatment approach (standardised treatment strategy, SDS). Plan of Investigation The plan comprises two components (laboratory- and clinic-based). In the laboratory-based component, mathematical modelling of our two previous amblyopia studies (MOTAS & ROTAS) will be used to develop PDS software. The clinic-based component will compare a SDS occlusion regimen with PDS regimens formulated by the PDS software in a three-phase randomised trial. It will involve 120 subjects (3-8 years) with amblyopia associated with strabismus, anisometropia or both recruited from West London hospitals under the care of consultants Miss Roberts & Miss Wren. Occlusion received will be objectively monitored by occlusion dose monitors previously developed by ourselves. Potential Impact It is estimated that in the UK alone over 35,000 children are newly diagnosed with amblyopia each year. If a PDS approach were shown to be practical and superior to the SDS approach it would be a highly significant advance in the management of the condition: the amount and duration of treatment could be minimised with clear benefits to the patient and with a potential gain in cost-effectiveness (reduced treatment time, increased effectiveness). The predicitve nature of the PDS approach can potentially transform the relationship between the family and clinician: the clinician being able to inform the family of the likely outcome and duration of treatment on the basis of the current prescribed dose, and concordance with such a dose.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: EYE
Title: Complex data management, knowledge extraction and computerised clinical decision support for chronic disease management
Funder: Department of Health (England)

Abstract: Monitoring chronic progressive diseases requires synthesis of complex data acquired over time to identify patients with an unfavourable clinical course by risk profiling, actual progression behaviour or by both. Because of data complexity and uncertainty of evidenced-based best practice, disease management is frequently suboptimal. Glaucoma, a chronic progressive neuropathy, causes irreversible blindness in a significant proportion of patients whilst under care. The project will: 1) provide analytical support to integrate and understand complex data, 2) evaluate patient-specific risk, 3) develop a clinical decision support system (CDSS) to improve evidence-based guideline adherence. The CDSS will prevent unnecessary glaucoma blindness by improving care quality.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE
Title: The Impact of Amblyopia: Reasons for not accessing treatment and the effect on developing literacy skills in young children
Funder: Department of Health (England)

Abstract: Poor vision in young children potentially affects their long term educational attainment, health and social outcomes. Early detection and treatment is recommended, however, many children fail to attend for treatment. I will explore factors influencing the occurrence of poor vision in young children and investigate why some children do not access treatment services. I will also assess the impact of poor vision on early developing literacy skills. The proposed research is nested in a birth cohort of 12000 Bradford children who are starting school. The evidence generated will inform a review and evaluation of alternative models of service provision.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: EYE
Title: Improving functional vision in patients with age related macular degeneration
Funder: Department of Health (England)

Abstract: Age related macular degeneration (AMD) is the leading cause of blind registration in the UK. Treatment is restricted to a small proportion of patients and rarely cures the condition. The project will improve visual capacity in patients with AMD by delivering an optimised home rehabilitation tool. It will employ computer-based methods to identify the best way of improving reading and facial recognition ability in patients with the condition. This will result in improved visual function and quality of life, fewer repeat clinic appointments, and a reduction in the substantial burden of the condition on the NHS.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: EYE