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Rohrer, B. et al.

Bärbel Rohrer, Qin Long, Beth Coughlin, R. Brooks Wilson, Yuxiang Huang, Fei Qiao, Peter H. Tang, Kannan Kunchithapautham, Gary S. Gilkeson, Stephen Tomlinson,

A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration.

PURPOSE: Polymorphisms in factor H (fH), an inhibitor of the alternative pathway (AP) of complement activation, are associated with increased risk for age-related macular degeneration (AMD). The authors investigated the therapeutic use of a novel recombinant form of fH, CR2-fH, which is targeted to sites of complement activation, in mouse choroidal neovascularization (CNV). CR2-fH consists of the N terminus of mouse fH, which contains the AP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. METHODS: Laser-induced CNV was analyzed in factor-B-deficient mice or in mice treated with CR2-fH, soluble CR2 (targeting domain), or PBS. CNV progression was analyzed by molecular, histologic, and electrophysiological readouts. RESULTS: Intravenously administered CR2-fH reduced CNV size, preserved retina function, and abrogated the injury-associated expression of C3 and VEGF mRNA. CR2 and PBS treatment was without effect. In therapeutically relevant paradigms involving delayed treatment after injury, CR2-fH was effective in reducing CNV and provided approximately 60% of the amount of protection of that seen in factor B-deficient mice that lacked functional AP. After intravenous injection, CR2-fH localized to sites of C3 deposition in RPE-choroid. CONCLUSIONS: Specific inhibition of the AP reduces angiogenesis in mouse CNV. Of note, intravenous injection of C3d-targeted CR2-fH is protective even though endogenous fH is present in serum at a higher relative concentration, and serum fH contains native C3d and cell surface binding domains that target it to cell surfaces. The most common AMD-associated variant of fH resides within a native cell-binding region of fH (Tyr402His). These data may open new avenues for AMD treatment strategies.[1]

References

A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration. Rohrer, B., Long, Q., Coughlin, B., Wilson, R.B., Huang, Y., Qiao, F., Tang, P.H., Kunchithapautham, K., Gilkeson, G.S., Tomlinson, S. Invest. Ophthalmol. Vis. Sci. (2009) [Pubmed]

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