Title: Development of novel tests to assess visual function in patients with inherited retinal degeneration.
Funder: Health Education England

Abstract: Background Inherited retinal degenerations (such as retinitis pigmentosa) are the leading cause of untreatable blindness in the working age population. Such conditions cause loss of peripheral vision, night vision, colour perception and other visual deficits that affect central vision as the disease progresses. There is currently no established treatment for these genetic conditions but novel therapeutic interventions such as gene replacement therapy are being trialled and have shown promise.Assessment of high contrast detailed vision, known as visual acuity (VA), is the preferred measure for assessing treatment outcome. The measurement of VA in patients with retinal disease can be variable due to the effects of loss of visual field, also caused by the disease. Therefore, it is important to develop strategies to improve the reliability of VA measurement in patients with retinal disease. In addition, patients with inherited retinal degenerations often retain good VA until late in the disease process so other measures are required for assessment. A broader range of visual outcome measures will provide a more thorough assessment of the impact of gene therapy in order to allow intervention at an earlier stage. Aims There are 2 primary aims being undertaken as 2 projects from the same cohort of patients. These will both impact on the wider gene therapy programme:Study 1: To characterise more precisely the types of visual function loss in patients with inherited retinal degeneration which can potentially be used in interventional clinical trials as outcome measures.Study 2: To investigate whether acquired visual field loss is associated with changes in the visual cortex using fMRI and establish the feasibility of including this assessment in interventional clinical trials.Investigational plan Study 1: An observational clinical study with participant frequency matching between a group of patients with retinal disease and a comparison group without retinal disease will be conducted to assess aspects of visual function. These will include: (i) More reliable assessment of visual acuity in the presence of visual field loss; (ii) low luminance VA (the ability to see details in low lighting); (iii) contrast sensitivity (the ability to distinguish items from the background); (iv) colour vision; (v) flicker fusion (how quickly cone photoreceptors responsible for daytime vision are able to respond to visual stimuli); and (vi) night vision. Test-retest reliability assessments will be conducted.Study 2: Eight patients with severe visual field loss (less than 10 degrees remaining) will be assessed using multiple types of fMRI scanning of the visual cortex to determine the presence of structural or functional changes. The value of the information gained will be assessed. The acceptability to patients of fMRI scanning and the feasibility of incorporating it into future gene therapy trials will be assessed.Potential benefits to patients and NHS A phase 1 gene replacement therapy trial, in which I am a co-investigator, has reported improvements in vision (Lancet, 2014), which are sustained over 4 years (New England Journal of Medicine, 2016). The data show that it can take several years to show a stabilisation in visual acuity in the treated eye versus a decline in the untreated eye. Visual function can be quantified with greater accuracy and precision in patients with inherited retinal degenerations using two approaches. Firstly reducing variability in the VA measurement allows more accurate assessment of VA. Secondly, the use of alternative assessments which probe the visual system in other ways may allow treatment effects to be seen on a shorter timescale. This will allow access to treatments for patients at an earlier stage of the disease process, such that quality of life and independence can be maintained.

Lay abstract: The retina is located at the back of the eye and contains light-sensing cells called photoreceptors that convert light energy to electrical signals. These signals are transmitted to the brain through the optic nerve and processed to allow us to see. If the light sensing cells are damaged then the light arriving may not activate the visual system correctly resulting in blindness. One of the most common forms of blindness in young people in the UK is genetic retinal diseases in which the light sensing cells die over time. The project is designed to understand what happens to visual function (the way we see) where there is retinal disease. There are two main aims, addressed in separate studies: Study one: The aim of study one is to undertake a thorough assessment of how vision changes following new treatments for genetic retinal diseases. This aim is important and timely because, although there is currently no established treatment for genetic causes of visual impairment, gene replacement therapy clinical trials are currently under way. This therapy replaces the missing or defective gene to allow the cells in the eye to work normally and has shown promising results for patients. It is essential to have reliable ways of assessing the outcomes of these clinical trials. Particularly important is an accurate measure of visual acuity. This refers to the ability to see fine details in black and white, and is measured using standardised letter charts similar to those used by opticians when testing the eyes. However, retinal diseases cause loss of peripheral vision (vision outside the central area) which can affect, in unpredictable ways, the ability to read across letter charts. This can lead to a large amount of variation each time visual acuity is measured which may make it difficult to get an accurate assessment. Thus alternatives will be explored, such as computer based charts with different types of presentation. Feedback from the patient focus group indicated that some of the tests currently used in assessing vision are difficult to perform and that aspects of vision that are important to them are not tested. These concerns will be addressed by developing or modifying a set of measures to assess a number of aspects of vision not currently part of routine examination: colour vision, speed of vision, ability to see contrast, and night vision. Together they will allow a more accurate assessment of the outcomes of new treatments, including small benefits or stabilisation of different aspects of vision. This will mean that therapies can be assessed and introduced into clinical practice in a shorter time frame, helping patients to retain as much quality of life and independence as possible. Study two: The second study aims to investigate whether long-term loss of peripheral vision, has an impact on the structure and function of the part of the brain that processes visual information (the visual cortex). Although the eyes are essential for vision, optical information is processed by the visual cortex. At the moment we do not know how a slowly changing abnormal input from the eyes to the brain changes the nature of the structure or function of the visual cortex. Magnetic Resonance Imaging (MRI) brain scans can help answer these questions by allowing us to visualise changes in the brain. This means we can determine how the brains of patients with retinal disease differ from those of people with healthy visual systems. We will assess whether it is possible to use MRI to perform scans to look at the visual processing performed by the brain and its structure. Multiple types of MRI scans will be conducted whilst participants are shown visual stimuli. This will allow us to assess the structure and function of the visual cortex in patients with reduced visual fields. A feasibility study will be conducted to explore whether MRI scans can be used in patients with genetic retinal diseases. We will also explore whether these MRI scans provide useful information for assessing outcomes of clinical trials. Sharing the results: Results from this work will be presented at conferences and published in scientific journals. They will also be presented to patient groups and the PPI panel will help to disseminate results to their organisations, locally and nationally, in person and online. The work will directly inform the gene therapy programme of the Clinical Ophthalmology Research Group, University of Oxford, in order to produce maximum benefit during the next planned gene therapy trial.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE