NIHRDataInsights/HRCSData huggingface dataset:
Title: Neuroprotective strategies: Amiloride Clinical Trial in Optic Neuritis (ACTION)
Funder: Multiple Sclerosis Society

Abstract: What is the project about? _x000D_ The aim of this project is to investigate the effect of amiloride as a new therapy for protecting nerves from damage following inflammation. Amiloride is a drug already used to treat heart failure and high blood pressure, so we know it's safe. The study will use imaging techniques to look at the effect of amiloride on nerve fibre loss in the retina of people following optic neuritis. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ Effective therapies for protecting nerve fibres from damage in MS are urgently needed. It is also important to find ways of quickly assessing these therapies. This project could develop amiloride as a neuroprotective therapy for MS._x000D_ _x000D_ The findings of this project will also pave the way for more clinical trials in the future.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;EYE
Title: Detecting retinal changes using OCT in ARSACS and other ataxias
Funder: Ataxia UK

Abstract: ARSACS is a rare inherited neurodegenerative disorder first described in Canada but now increasingly recognised in other populations including in the UK. A characteristic feature of the Canadian ARSACS cases is change in the retinal nerve fibre layer at the back of the eye which can be detected by OCT. This technique is quick, cheap, non-invasive, painless and readily available in most eye clinics. By contrast, the genetic test for ARSACS is expensive and not readily available in most NHS hospitals. The first aim of this project is to investigate whether OCT could be used as a screening test for ARSACS, to decide whether to send for the formal genetic test. However, the retinal changes seen in Canadian cases of ARSACS appear to be less frequent in non-Canadian cases and may be seen in unaffected family members who carry one copy of the abnormal ARSACS gene (so-called ‘carriers’). It is therefore vital to know whether these retinal changes are a reliable indicator for ARSACS amongst the population of people who are routinely assessed in the Ataxia Clinic. It is therefore important to study patients with ARSACS, the unaffected family members of patients with ARSACS who might be carriers of the gene, but also patients with other (usually genetic) causes of ataxia which have a presentation similar to ARSACS who might be undergoing the same diagnostic work-up (eg Friedreich’s or spinocerebellar ataxia). Studying these patients will also give us important information on the retinal changes and visual symptoms of these patients which can improve the information we give in clinic. Furthermore, this study will allow us to investigate whether OCT findings are related to different ARSACS mutations, disease severity or duration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;EYE
Title: Role of dopamine and LRRK2 mutants in the decline of vision
Funder: Parkinson's UK

Abstract: The most common genetic cause of Parkinson's disease (PD) is a mutation in the LRRK2 gene, G2019S. We have therefore developed a new fly model, which exploits the homology of gene and visual organization between fly and human. It shows rapid decline in electroretinogram performance with G2019S expression, but not with other mutations in LRRK2. This loss of visual function is most marked when G2019S is expressed in the dopaminergic neurons. Remarkably, when G2019S is expressed in dopaminergic neurons it is the non-dopaminergic photoreceptors which are most affected, indicating a spreading pathology. Our aim is to test the hypothesis that it is the interaction between dopamine and G2019S which leads to neuronal death. We will use the extensive fly genetic toolbox to manipulate dopamine levels, to test the function of G2019S as a dominant negative kinase mutation, and to examine the role of neural activity in accelerating the speed of degeneration. We will support this by using drug application (L-DOPA, kinase inhibitors, glycolytic upregulation). We will examine the way in which the pathology spreads form neuron to neuron using confocal imaging of dopaminergic terminals. This will provide a new view of LRRK neurophysiology in the whole organism, in a way that has not been possible in mouse models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EYE
Title: Development of an AAV vector for treatment of Batten disease caused by mutations in TPP1 (CLN2 disease)
Funder: Wellcome Trust

Abstract: Dr Sara Mole of University College London is seeking to develop a gene therapy for CLN2 disease. This is one type of Batten disease, an inherited disease that affects young children. The aim is to prevent the Joss of vision that usually occurs as part of this disease as this will improve the quality of life for the children and their families. The work will build on experience that has Jed to clinical trials for other types of blindness, to make a vector that can deliver a healthy copy of the defective gene tothe eye of an animal model with the same disease. The research will test that this is safe and does not cause any problems in the eye. We will/earn more about the effect of the disease on the eye and the effectiveness of this approach at preventing or slowing down the Joss of vision. The results may help to develop gene therapy to treat other symptoms of the Batten disease and other types of disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL;EYE
Title: Synaptic transfer of visual information
Funder: Medical Research Council

Abstract: Our research focuses on the mechanisms controlling neurotransmitter release at the synapse; the way these mechanisms determine the processing of information by a neural circuit, and plasticity of that circuit. These topics are investigated in the retina, using genetically modified zebrafish expressing fluorescent proteins that report the fusion and retrieval of synaptic vesicles and the presynaptic calcium signal triggering these processes. Using isolated cells, we monitor the synaptic vesicle cycle in real-time at the level of individual vesicles, with the aim of identifying the molecular interactions that control their docking, priming, fusion and retrieval. Using live zebrafish, we monitor activity across arrays of interconnected neurons in the retina, with the aim of understanding the synaptic interactions that process visual information. Coordination of these two approaches provides the opportunity to understand how the processes that regulate neurotransmitter release from the presynaptic terminal contribute to plasticity of the retinal network as it adapts to visual stimuli.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EYE
Title: Development of stem cell therapy to restore photopic vision
Funder: Medical Research Council

Abstract: Retinal degenerations leading to loss of photoreceptors are the leading cause of untreatable blindness in Europe. Currently there are no treatments that restore lost photoreceptors and visual function. There is clearly a need for new therapeutic approaches. In 2006 we discovered that photoreceptor precursors can be effectively transplanted into the adult retina and recently we have been able to provide the first definitive evidence of restoration of rod-mediated vision, following transplantation into Gnat1-/- animals, a model of congenital stationary night blindness. Our research to date has established principles of effective rod photoreceptor transplantation. We propose that retinal repair by photoreceptor transplantation is one of the most feasible types of CNS repair as new photoreceptors need only make short, single synaptic connections to the inner retinal circuitry to contribute to visual function. As humans rely on cone and not rod vision, cone transplantation is likely to be the most effective strategy for clinical application. We are now seeking to prove the concept that it is possible to restore photopic vision in mouse models of human retinal degenerative diseases by cell transplantation based on our proven strategy for rod transplantation. The following inter-related investigations will be conducted: (i) modify environmental conditions to enhance cell integration and migration (ii) manipulate the genetic controls that limit cone integration, including transplantation of Nrl-/- and Nr2e3-/- cells, lineage tracing and using genetics fluorescent reporters (iv) examine retinal circuitry of transplanted cells using new synaptic labeling methodologies that utilise engineered viral vectors to transduce cells through connecting synapses. (v) transplant photoreceptor precursors generated from ES/iPS cells and demonstrate that that they are functional. This programme aims to provide the framework for developing stem cell therapy to treat human retinal disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL;EYE
Title: Development of a small molecule combinatorial treatment for RGC survival and axon regeneration to restore sight after optic neuropathy
Funder: Medical Research Council

Abstract: We aim to develop a treatment to promote retinal ganglion cell (RGC) survival and restoration of visual function in a rat model of optic nerve injury. RGC regeneration has been demonstrated in response to neurotrophin administration and ocular inflammation and genetic studies have implicated the mTOR signalling pathway in neuronal regeneration. Knockdown of SOCS3, a negative regulatory molecule may potentiate this mechanism. The objectives are to develop a combinatorial molecule to a triple RGC axogenic/neuroprotective combination of siRNAcasp2/siRNARedd1/2/shRNASOCS3/AAV2cntf and test this in our rat model to monitor neuronal survival, regeneration and re-innervation of central targets with restoration of visual function. Study 1: test for SOCS3 knockdown in RGC by transfecting retinal cultures with a synthesised siRNA for SOCS3 and performing Western blots and detection of relevant protein bands using specific antibodies against SOCS3. Study 2: in vivo evaluation of SOCS3 knockdown, by constructing an AAV short hairpin RNA targeting SOCS3 mRNA. After intravitreal injection we will evaluate RGC transduction rates and knockdown of SOCS3 by RT-PCR and western blotting. Study 3: development of pupillary constriction measurement and assessment of visually guided behaviour by standard water maze tasks. Study 4: evaluation of anatomic restitution and return of visual function after intravitreal delivery of the combinatorial nucleic acid treatment in optic nerve transected rats. Treated rats will be compared to control groups at defined time periods following optic nerve crush. FluroGold backfilled RGC indicating RGC survival, visually guided behaviour, immunostaining for re-innervation of central targets and electrophysiological assessment of visual pathway function will be evaluated. Results will have implication to axonal regeneration in the CNS as a whole and be translated into clinical treatments for patients with diseases that are presently untreatable.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;EYE
Title: Assessing the therapeutic efficacy of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in idiopathic intracranial hypertension (IIH).
Funder: Medical Research Council

Abstract: Idiopathic intracranial hypertension (IIH), is a common condition of unknown aetiology affecting the young obese female population (20 per 100,000). Faced with the global obesity epidemic, its incidence is expected to rise further. IIH is characterised by elevated intracranial pressure (ICP) which manifests as disabling headaches and severe visual loss in up to 25% of patients. An evidence base for treatment has not been established and there are currently no effective and tolerable pharamcotherapeutic options. Based upon our in-vitro observations, we have hypothesised that increased local glucocorticoid generation through the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within the choroid plexus that generates cerebrospinal fluid (excess production leading to raised ICP) is crucial to the pathogenesis of IIH. This mechanism is analogous to that occurring in the ocular ciliary body which produces aqueous humor where 11beta-HSD1 inhibitors have been shown to lower intraocular pressure. We have recently published a seminal study in patients with IIH and demonstrated that weight loss significantly reduced 11beta-HSD1 activity, ICP and dramatically improved patient symptoms; the observed reduction in ICP correlated directly with the reduction in ICP. In collaboration with our industrial partner, AstraZeneca (AZ), we will conduct a double blind, placebo controlled randomised phase II study to assess the tolerability, safety and efficacy of the selective 11beta-HSD1 inhibitor, AZD4017, in the treatment of IIH. The study will be conducted at University Hospitals Birmingham NHS Foundation Trust, the Midlands Eye Centre and the Wellcome Trust Clinical Research Facility. In total, 24 patients with active chronic IIH (raised ICP and papilloedema) will be randomised to AZD4017 or placebo tablets (1:1).The primary outcome measure, intracranial pressure, will be evaluated by lumbar puncture at 12 weeks compared to baseline.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;EYE
Title: Bristol Vision Institute Laboratory.
Funder: Wellcome Trust

Abstract: Humans are highly visually driven animals. The question of how we perceive the visual world around us and how we use our visual sense to guide behaviour is of immediate interest and relevance. Vision is studied by a wide range of experts like physiologists, psychologists, computer scientists and engineers. Only by combining methods from these varied disciplines can we hope to get a full understanding of the complex underlying issues. The University of Bristol has founded a Bristol Vision Ins titute to facilitate interaction and collaboration between academic disciplines. Within the institute it is now recognised that a shared laboratory space would help experts with different backgrounds work together, learn from each other s methods, and in this way enhance our knowledge of the workings of the visual system, how it contributes to everyday action, and how it affects behaviour in case of disease. This proposal aims to provide for a state-of-the-art facility that allows scientis ts to create a wide variety of visual environments and then measure everyday behaviour within such environments (e.g. walking, eye-hand co-ordination, etc.). This more naturalistic approach ensures practical problems to be addressed, which will be of benefit to the wider community.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL;EYE
Title: Measurement and modelling of centre and surround mechanisms in human visual cortex.
Funder: Wellcome Trust

Abstract: Our perception of sensory stimuli is greatly influenced by context. A colour that is vivid and vibrant against a gray background may seem dull and drab against other colours; a conversation in a noisy room would sound like screaming without the background noise. In vision, such contextual effects are present at all levels from low level features like contrast and luminance, mid-level features such as orientation, to high-level features such as the the perceived size and shape of objects and fa ces, the presence of other stimuli in the visual field strongly influence how stimuli are perceived. Although the neuronal mechanisms that underlie some contextual effects (for example, why the perceived brightness of a coloured patch depends on the brightness of its surroundings) are well understood, most are not. In particular, the mechanisms behind higher-level context effects such as how other faces appear more feminine after prolonged viewing of a male face are mostly unknown, in part b ecause most of our knowledge about the mechanisms come from experiments in monkeys rather than humans. This research project will study the mechanisms behind contextual effects in the visual cortex of humans, using a technique known as functional magnetic resonance imaging.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;EYE
Title: Alpha2-chimaerin as a molecular switch which regulates motor axon growth and guidance.
Funder: Wellcome Trust

Abstract: During nervous system development, motor neurons grow extensions called axons which navigate over long distances to wire up with muscles. Nerve navigation depends on a system of guidance signals in the environment. In order to devise strategies to repair the diseased or degenerating nervous system, we need to understand the molecular details of this guidance process, and how it can go wrong. In humans three cranial nerves control the muscles which move the eyeball, and when this system develo ps incorrectly, it results in squint. We have discovered that patients with a congenital form of squint (Duane Syndrome) carry mutations which lead to malfunction of the molecule alpha2-chimaerin. Alpha2-chimaerin acts inside neurons to transmit guidance signals, but it is not known which signals and receptors function in the wiring of the eye muscles. Our idea is that repellent and attractant signals converge on alpha2-chimaerin, which co-ordinates the patterning of these connections. We w ill identify the molecular signals and the axonal receptors they bind to, as well as discovering how alpha2-chimaerin interprets and modulates these signals. We will also study why alpha2-chimaerin malfunction results in very specific cranial nerve defects, expanding our basic science knowledge and informing future therapies for squint.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EYE
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Restoring light sensitivity to the degenerate retina using gene therapy'.
Funder: Wellcome Trust

Abstract: The proposed project will assess the potential to induce light sensitivity in human non-photoreceptor neuronal cells through gene transfer of melanopsin (OPN4), a light sensitive pigment. The purpose is to develop preclinical data that could subsequently be used to support a clinical trial application to treat patients who are blind from retinitis pigmentosa (RP). An adeno-associated viral (AAV) serotype 5 vector will be generated, initially driving Green Fluorescent protein (GFP) reporter gene expression. Two in vitro models will be established (a human neuronal cell line in culture and also in explants of partly degenerate human retina harvested from patients with informed consent though a recently approved clinical study) on which the vector will be tested. Subsequently a vector containing the human melanopsin gene in an expression cassette containing a promoter and regulatory elements already shown to be effective in transducing bipolar and horizontal cells of the retina will be tested. Light sensitivity will be assessed and optimised using patch clamping and calcium imaging of the in vitro models. In order to optimise efficacy in vivo, subretinal injections of the vector will be administered to mice with retinal degenerations, and light sensitivity assessed.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL;EYE
Title: Colour appearance in a dynamic world.
Funder: Wellcome Trust

Abstract: Careful inspection of two photographs of Durham cathedral, one taken at midday and one at sunset reveals that the same stone surface can produce a large variety of colours in the image. Yet we tend to interpret these colours as representing the same surface under illumination that differs in its spectral and geometric properties. The goal of sensory perception is to reliably estimate the properties of objects in the world. This is a huge computational problem, primarily because of ambiguity in t he retinal input. Yet, the human brain solves it rather well. We argue that consideration of time-varying signals is critical to understanding the information available from the visual input and the nature of the neural mechanisms that might extract this information. Most research in this area has used snapshot images of visual scenes. However, events in the world unfold over time - lighting can change from moment to moment, and our own eye-movements direct a succession of different images to th e foveae as we scan the scene. The associated changes in the retinal image are not random, and we test whether their temporal structure provides information to disambiguate properties of objects and of the lights that illuminate them.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;EYE
Title: The functional organisation of synaptic connectivity in visual cortex.
Funder: Wellcome Trust

Abstract: Research in my lab is part of an increasing worldwide effort to understand thewiring of brain circuits. This work may uncover how the brain perceives. Specialised brain regions compute different kinds of information (images, sounds, touch, movement), each containing millions of brain cells (neurons) making trillions of connections (synapses) between them. One way to make sense of this humbling complexity is to discover the rules by which neurons with different roles in the brain interact with each other but this has proved a major technical challenge. We have developed a powerful new method for measuring synaptic connections between neurons with known functional roles in the network. We will use this method to study the mechanisms of vision. By discovering how neurons which are sensitive to different visual features (e.g. edges in images) connect to each other and how these connections give rise to the function of the cells, we hope to uncover the principles of how images are built up in the brain. In the future, our new method can be used to reveal the wiring of other brain regions, and help to understand how wiring is altered in devastating diseases such as Schizophrenia, autism and epilepsy.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;EYE
Title: High Resolution Retinal Imaging.
Funder: Wellcome Trust

Abstract: Retinal imaging in patients and animal models of retinal dysfunction advances our understanding of diseases affecting vision and provides a window to the brain to study degenerative central nervous system disease. We request funding to obtain five cutting-edge retinal imaging devices that can visualise cellular and subcellular structures and dynamic processes in living retinal cells ex vivo and permit non-invasive high resolution in vivo imaging at single cell resolution in patients and small an imal models. Each of these devices offers new and unprecedented research opportunities due to recent advances in imaging technology. When combined into a single platform, these devices will afford capability not previously available in the UK and significantly enhance a wide variety of Wellcome Trust-funded fundamental, translational and clinical research programmes. The key objectives of the proposal are therefore to establish high resolution retinal imaging i) in patients to facilitate world-l eading research in retinal disease and therapeutics; ii) in animal models to elucidate disease processes and identify novel therapeutic targets; and iii) in living cells to investigate disease mechanisms. Achieving these objectives will add value to currently funded Wellcome Trust research programmes aimed at understanding the brain and retina and identify new therapeutic strategies.


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