Research Project
7218775
[unreadable] DESCRIPTION (provided by applicant): The overall goal is to develop monoclonal antibody-based compounds capable of blocking human MASP-2 function as potential therapeutic agents for the treatment of age-related macular degeneration (AMD). MASP-2 is a plasma serine protease uniquely required for complement activation via the lectin pathway and may be an attractive target for the development of novel therapeutics for inflammatory disorders. The complement system is an important host defense mechanism; however, excessive or uncontrolled complement activation can trigger an intense inflammatory response that is thought to significantly contribute to undesired tissue damage in many disease states. Recent results implicate a central role for complement activation in the pathogenesis of AMD, and especially of choroidal neovascularization (CNV) the most serious form of AMD. Three pathways have been described for complement activation: the classical, alternative and lectin pathways. To treat AMD it would be desirable to develop pathway-specific inhibitors which would target only the complement pathway causing the particular pathology without completely shutting down the immune defense capabilities of complement. Immunohistological studies of human donor tissues indicate that the classical pathway does not play a major role in triggering complement activation in AMD. Recent studies indicate that the lectin pathway may have a critical role in triggering complement activation in many tissue injury settings, especially when there is no evident role for the classical pathway in the disease pathogenesis. A mouse genetically-deficient in the MASP-2 protein has been developed. The availability of the MASP-2 (-/-) mouse and the genetically-matched MASP-2 (+/+) mouse provides a powerful research tool to directly evaluate the pathogenic role of MASP-2 and the lectin-dependent complement system in murine models of CNV and AMD. The specific objectives in this SBIR grant application are to compare and contrast the results obtained when MASP-2 (-/-) and MASP-2 (+/+) mice are evaluated in the course of laser-induced CNV, an accelerated model of neovascular AMD. A successful outcome in the Phase I studies would indicate that MASP-2 is an attractive therapeutic target for the treatment of the CNV (wet) form of AMD. A Phase II application would focus on the development of blocking monoclonal antibody-based compounds specific for MASP-2 as potential therapeutic agents for AMD. Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 and it is estimated that 1.75 million individuals suffer from this disease in the United States, with another 7 million "at risk". In this SBIR grant, studies will evaluate a potential new target called MASP-2 for treatment of AMD. Studies will be conducted in mice deficient in MASP-2 to determine their susceptibility to AMD and would provide support for this as a novel target in AMD medication development. [unreadable] [unreadable] [unreadable]
