Age-related macular degeneration (AMD) is the number one cause of blindness for the elderly population over 60. The primary damage in AMD occurs in the retinal pigment epithelium (RPE). There are two forms of AMD, the dry and the wet form, the latter being associated with choroidal neovascularization (CNV) and responsible for 90% of the blindness. AMD is a complex disease involving multiple genes. Expression profiling is a powerful approach to complex multi-gene diseases, when biological concepts are combined to identify genes fulfilling multiple criteria. Since daily phagocytosis of photoreceptor outer segments (OS) is a key function of RPE, and genes that play a role in the pathogenesis of AMD would be expected to show expression changes, we used a custom expression profiling strategy called CHANGE to identify candidate AMD genes fulfilling both criteria. Membrane-type matrix metalloproteinase I (MT1-MMP) was a gene identified by this strategy that showed 1) involvement in OS phagocytosis, 2) increase that correlated with the degree of pathology in AMD, and 3) increase in another retinal degeneration, the RCS rat model. A Tet-On conditional over-expression transgenic mouse model of MT1-MMP was constructed to confirm the pathogenic potential of this candidate gene. Induction of MT1-MMP over-expression by doxycycline administration in the model demonstrated dramatic vacuolar degeneration, proliferation, and migration of RPE, leading to CNV, resembling characteristics seen in AMD, within days of induction. MT1-MMP is a plausible candidate for AMD since 1) it is the primary activator of MMP2 which has been shown to be increased in the interphotoreceptor matrix and chorioneovascular membranes of AMD patients, 2) it is an important mediator of cellular migration for endothelial cells in blood vessel formation, making it relevant to CNV, 3) it up-regulates VEGF which has been shown to be important in wet AMD, and 4) it has activities against various other matrix components, and the importance of matrix has been demonstrated in AMD-like Sorsby's fundus dystrophy. Thus, we believe MT1-MMP to be an important new therapeutic target for AMD. This STTR application represents the Phase I of a project to develop in collaboration with iTherapeutics the potential dual commercial benefit of our discovery, namely 1) a model of AMD choroidal neovascularization in which the CNV can be easily and quickly induced by a simple administration of doxycycline for testing of various therapeutics against the wet form of AMD, and 2) anti-MT1-MMP agents as potential therapeutics for AMD.
The aims for Phase I will focus on 1) above with Specific Aim 1, to select the best line of the transgenic model among the 3 selected lines for induction of MT1-MMP over-expression and consistency of phenotypic expression, and Specific Aim 2, to confirm the phenotype of progressive degeneration of RPE and CNV in the model through histological, immunological, and molecular analyses. For Phase II, we will pursue 2) above, using our model as a template.
Age-related macular degeneration, especially the wet form, is the number one cause of blindness for the elderly population over 60. This project whose aim is to develop a powerful animal model of AMD that can be used for testing of therapeutics for wet AMD and to use it to identify a new effective therapeutic for wet AMD is highly relevant to public health of the elderly. ? ? ?
| Dodge, James C; Haidet, Amanda M; Yang, Wendy et al. (2008) Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol Ther 16:1056-64 |
