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Originally published In Press as doi:10.1167/iovs.08-2222 on March 5, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:3056-3064.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2222
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A Targeted Inhibitor of the Alternative Complement Pathway Reduces Angiogenesis in a Mouse Model of Age-Related Macular Degeneration

Bärbel Rohrer,1,2 Qin Long,1 Beth Coughlin,1 R. Brooks Wilson,1 Yuxiang Huang,3 Fei Qiao,3 Peter H. Tang,2 Kannan Kunchithapautham,1 Gary S. Gilkeson,4 and Stephen Tomlinson3

1From the Departments of Neurosciences/Division of Research, 2Ophthalmology, 3Microbiology and Immunology, and 4Medicine/Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina.

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.






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