Chong, Ngai Hang Victor; (2002) Retinal degeneration: Models and therapies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Retinal degeneration is one of the leading causes of blindness in the developed world. There is currently no effective therapy. In order to improve our understanding of these conditions, we characterised three animal models of retinal degeneration, namely pigmented retinal degeneration slow (rds) mouse, retinal dystrophy (Rdy) cats and the miniature longhaired dachshund dog (MLHD). We then carried out a series of treatment trials using both inhibitors of caspases and neurotrophic factors in these animals. Using immunohistochemical techniques, there was mis-localisation of opsin, reduction of synaptophysin in the outer plexiform layer and increased expression of glial fibrillary acidic protein in Muller cells in all of these animal models. Apoptosis was found to be the main mode of photoreceptor cell death. Photoreceptors in the pigmented rds mouse were found to degenerate more slowly than the albino rds mouse. The Rdy cats had opsin labelled neurites similar to those described in human retinal degeneration. The MLHD dog was demonstrated to have a cone-rod dystrophy (CORD) based on electrophysiological studies. It represents the first animal model of CORD. As apoptosis is the main mode of cell death, we attempted to either block the apoptotic pathway by caspases inhibitors or prevent photoreceptors entering the apoptotic pathway using neurotrophic factors. It appears that DEVD, a caspase-3 inhibitor, might slow photoreceptor cell loss in the pigmented rds mice, but z-VAD and YVAD did not. We have also found that Axokine, a ciliary neurotrophic factor analogue, might prolong photoreceptor cell survival in the Rdy cats, but brain derived neurotrophic factor had no effect. Furthermore, Axokine appears to preserve retinal function in the MLHD dogs as measured by electroretinography for a short period of time after an initial suppression.

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