Novel Mouse Models of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among those over 65 in the U.S., Western Europe, and Japan. It affects over 11 million persons in this country alone, and with the aging population will exact a greater toll. The absence of a faithful animal model has hampered the study of AMD and the development oftherapeutics. We have discovered two strains of genetically modified mice that develop many features of AMD as they age. Elderly mice (9 - 24 months) deficient either in the monocyte chemoattractant protein-l (MCP-I) or CC chemokine receptor-2 (CCR2) genes develop lipofuscin (autofluorescent lysosomal storage bodies in the retina), drusen (lipoproteinaceous deposits between the retina & choroid), and thickened Bruch's membrane (an extracellular matrix between the retina and choroid), the earliest manifestations of AMD in humans, as well as choroidal neovascularization, the late exudative, blinding form of AMD. These lesions are ophthalmoscopically, angiographically, and histopathologically similar to those in patients with AMD. These pathologies are absent in age-matched wildtype mice and several other knockout strains. We hypothesize that the accumulation of drusen and lipofuscin associated with senescence is normally cleared by the recruitment of scavenger macrophages, which is impaired in the absence of MCP-l or its receptorCCR2, and that rescue ofMCP-1 or CCR2 function can regress AMD. These hypotheses will be directly tested by (1) characterizing the temporal development of AMD features in MCP-I or CCR2 - /- mice fTomages 9 to 24 months by ophthalmoscopy, angiography, and histopathology, compared to wildtype age-matched mice, and (2) testing whether rescue ofMCP-1 or CCR2 function will lead to regression of AMD in elderly MCP-I or CCR2 -/- mice. The rescue strategies will include intraocular injection of an adeno-associated viral vector coding for MCP-I in elderly MCP-I -/- mice, systemic delivery ofMCP-1 via osmotic pumps in elderly MCP-I -/- mice, or introduction ofCCR2 bearing stem cells capable of differentiating into macrophages into bone marrow-ablated CCR2 -/- mice. These mice represent the first faithful models of both early and late AMD. As such they can provide mechanistic insights into the development AMD and assist in efficacy testing of candidate drugs.