Sorsby fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is characterized by bilateral loss of central vision as a consequence of choroidal neovascularization (CNV). Specific mutations in the TIMP-3 gene involving exon 5 or the intron4-exon5 boundary have been shown to be causative. Early this year, the AMD consortium identified rare coding variants in the TIMP3 gene when analyzing 16,144 patients and 17,832 controls. In addition, they identified the first genetic association signal specific to wet AMD near MMP9. The clinical and histopathological similarities between AMD and SFD and the identification of variants in the matrix metalloproteinase pathway in AMD suggest that similar downstream effectors might be in play in both conditions. A better understanding of the pathophysiological mechanisms contributing to the CNV in SFD will provide information that could be potentially useful in AMD. In comparative studies using TIMP-3 deficient mice, S156CTIMP-3 transgenic mice and in vitro culture experiments we have determined that TIMP-3 partially inhibits angiogenesis by blocking the binding of VEGF to VEGR-2. S156C TIMP-3 mutant protein induces angiogenesis via VEGF and bFGF. We have also shown that the absence of functional TIMP-3 results in an accumulation of hyaluronan that regulates choroidal vasculature. Based on these results, we hypothesize that TIMP3 is required to control and localize matrix degradation in the RPE/choroid, and loss of TIMP3 function in this regards leads to an abnormality in growth factor/angiogenesis factor, increased HA signaling and neovascularization.
Sorsby fundus dystrophy is a rare disease with striking similarities to age-related macular degeneration. Choroidal neovascularization (CNV) occurs in about 20% of patients with AMD but accounts for the majority of vision loss in the disease. The exact molecular and pathological mechanism(s) that lead to CNV have not yet been identified. Almost all patients with SFD develop CNV and therefore it is a useful model to examine the pathophysiology of this phenotype. The knowledge gained from these studies will not only contribute to our understanding of fundamental principles of neovascularization, but may also lead to the development of new therapeutic approaches for SFD as well as AMD and other diseases in which angiogenesis play a critical role.
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