| There is a group of retinal degenerative diseases which affects the macula with particular severity and is characterized by degeneration of the neural retina, retinal pigment epithelium (RPE), and choriocapillaris. Because the maicula contains the area of maximum visual acuity and subserves central vision, which provides the vast majority of visual information, these diseases are an especially devastating form of blinding disorder. The most common member of the group is age-related macular degeneration (AMD). In fact, it is the most common cause of blindness in developed countries. Treatment is limited and there is no cure. Development of therapies has been hindered by lack of proper animal models.; Sorsby's fundus dystrophy (SFD) is a retinal degenerative disease which involves the entire fundus and has many pathological features similar to those of AMD. Unlike AMD, a genetic basis has been determined. It is caused by autosomal dominant mutations in the tissue inhibitor of metalloproteinases-3 (TIMP-3). TIMP-3 helps modulate turnover of extracellular matrix in various tissues throughout the body, including the eye. This information was exploited to generate an animal model for SFD, mice transgenic for wild type and mutant (G167C, Y172C) TIMP-3. Several lines of mice for each transgene were established. After genomic integration and expression of the transgenes in the appropriate tissues were confirmed, the mice were studied by ophthalmoscopic examination and histopathological analysis of eye tissue.; One line of mice, TgTlMP3mP1 31M/172, developed several pathological features highly reminiscent of SFD, including subRPE deposits, choroidal neovascularization (CNV), and retinal degeneration by eight months of age. Retinal changes in the form of pale fundus spots and displaced retinal nuclei were observed by as early, as one month. Mice transgenic for wild type or G167C mutant TIMP-3 have not exhibited pathology yet. Significantly, mice of line 31M/172 are the first animals created which model a hereditary human retinal disease characterized by CNV, which causes 80--90% of the blindness resulting from AMD. These mice have good potential for serving as a model of SFD and AMD. They provide the valuable opportunity to understand disease mechanism and progression and test treatments for these disabling disorders. |
