Development of Complement Modulating Therapeutics for AMD Factor H is the principal soluble inhibitor of the complement cascade alternative pathway, an important component of the innate immune system. In recent months, several groups have discovered that variations in the Factor H gene (CFH/HF1) are a major genetic susceptibility factor for age-related macular degeneration (AMD), the most common cause of blindness worldwide, and for membranoproliferative glomerulonephritis type II (MPGN II), a renal disease characterized by ocular features that are indistinguishable from those associated with AMD. A major """"""""risk"""""""" CFH haplotype that confers increased susceptibility to AMD and two """"""""protective"""""""" haplotypes that confer a decreased risk, have been defined. These findings provide strong support for our earlier hypothesis that activation of the complement cascade contributes to the progression of AMD. We have designed a series of translational studies to clarify the role of CFH in the pathogenesis of AMD. The proposed studies will test the central hypothesis that the risk CFH haplotype gives rise to quantitative or functional alteration(s) in the CFH protein which result in uncontrolled complement activation and bystander injury to the macula in individuals with AMD, resulting in degeneration and loss of vision. We propose to explore the concept that replacing or augmenting the complement modulating activity the dysfunctional CFH protein should be effective in preventing or delaying the pathology associated with AMD and MPGN II. This is the long-term goal of the proposed interdisciplinary collaboration. The essence of these aims meet the primary stated goal of the """"""""NEI Translational Research Program on Therapy for Visual Disorders"""""""" which is """"""""to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for complex visual system disorders and disease"""""""". The framework for this program consists of six interrelated Modules. In the first Module, we will improve and expand our existing repositories of eye tissues, plasma, sera, urine, RNA, and DNA from donors and well-characterized families and cohorts of patients with AMD, MPGN II, and other potentially related, immune-mediated diseases. In addition, we propose to develop or acquire relevant biological reagents, tools, and model systems with which to pursue these studies. In Modules II-VI, we will use these new resources to solidify our understanding of how dysregulation of the complement alternative pathway, and of CFH in particular, confers increased susceptibility to AMD and other diseases. The outcome of these studies will serve as a platform for the identification of new biomarkers and drug targets (Modules V-VI) that will hasten the development of clinically effective diagnostics and pharmaceutical agents for the treatment of AMD. ? ? ? ?
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