Pathology and treatment of mouse models of dominant retinal disease

Hereditary retinal disease affects our most precious sense, sight, in about 1 in 3000 of the population. Many of these disorders cause complete loss of vision blindness and, unfortunately, there is as yet no effective treatment. A major difficulty in developing treatments is the inability to sample retinal tissues from patients in order to fully understand how the disease develops or to test novel treatments that may further compromise limited vision. The use of animal models avoids these problems but, to be meaningful, they need to accurately mimic the human disorder. This means that the same gene mutation must be studied. Such mutations are generally not found in nature so the same gene as in human must be targeted in the animal so that the same mutation is introduced. These are complex, time-consuming and expensive experiments, so it is important that such models of human disease are fully exploited. We have already generated two such models with human mutations in genes responsible for basic visual processes resulting in the loss of light sensitive cells in the retina. We propose to use these models to gain a detailed understanding of the process of retinal degeneration and to follow this with an assessment of potential treatment options that will include the testing of various drugs, growth factors and gene replacement therapy using viral vectors delivered to the eye. This will enable us to determine the treatment for patients and will provide the first step towards a clinical trial.

Inherited retinal disease is a major cause of blindness, especially amongst children and at present, there is no effective treatment. Progressive loss of vision is a feature of many of these disorders with loss of photoreceptors cells and retinal dystrophy as the most likely pathology. There is however little detailed information on disease progression in patients as invasive examination of the retina is not possible, and the testing of novel treatments is ethically unacceptable. Animal models provide therefore the only way forward and the objective of the proposed project is to obtain detailed information on the progression of inherited retinal disease through the study of two mouse models that each carry a human disease mutation previously introduced by gene targeting. The diseases show a dominant pattern of inheritance and our preliminary data confirm that that these models replicate the progression of the disorders in patients. This information obtaiend from these studies will then be used for a detailed assessment of disease mechanisms and the development of novel treatments. The steps in this process are as follows:
1. To characterise fully the deleterious effects of gene mutation on retinal function using a variety of techniques including electrophysiology, biochemistry, microscopy and histology to determine the precise mechanism of retinal degeneration.
2. To use the fully characterised mouse models to assess the efficacy of different management and treatment regimens, including light/dark cycle, drugs, neuroprotection with growth factors, transcriptional interference via microRNAs, and gene therapy with AAV vectors.