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.
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 mousefH, 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.
Authors: Mingyao Li; Pelin Atmaca-Sonmez; Mohammad Othman; Kari E H Branham; Ritu Khanna; Michael S Wade; Yun Li; Liming Liang; Sepideh Zareparsi; Anand Swaroop; Gonçalo R Abecasis Journal: Nat Genet Date: 2006-08-27 Impact factor: 38.330
Authors: Nalini S Bora; Sankaranarayanan Kaliappan; Purushottam Jha; Qin Xu; Baalasubramanian Sivasankar; Claire L Harris; B Paul Morgan; Puran S Bora Journal: J Immunol Date: 2007-02-01 Impact factor: 5.422
Authors: Dominiek D G Despriet; Caroline C W Klaver; Jacqueline C M Witteman; Arthur A B Bergen; Isabella Kardys; Moniek P M de Maat; Sharmila S Boekhoorn; Johannes R Vingerling; Albert Hofman; Ben A Oostra; André G Uitterlinden; Theo Stijnen; Cornelia M van Duijn; Paulus T V M de Jong Journal: JAMA Date: 2006-07-19 Impact factor: 56.272
Authors: Peter J Coffey; Carlos Gias; Caroline J McDermott; Peter Lundh; Matthew C Pickering; Charanjit Sethi; Alan Bird; Fred W Fitzke; Annelie Maass; Li Li Chen; Graham E Holder; Philip J Luthert; Thomas E Salt; Stephen E Moss; John Greenwood Journal: Proc Natl Acad Sci U S A Date: 2007-10-05 Impact factor: 11.205
Authors: John R W Yates; Tiina Sepp; Baljinder K Matharu; Jane C Khan; Deborah A Thurlby; Humma Shahid; David G Clayton; Caroline Hayward; Joanne Morgan; Alan F Wright; Ana Maria Armbrecht; Baljean Dhillon; Ian J Deary; Elizabeth Redmond; Alan C Bird; Anthony T Moore Journal: N Engl J Med Date: 2007-07-18 Impact factor: 91.245
Authors: Beverly E Prosser; Steven Johnson; Pietro Roversi; Andrew P Herbert; Bärbel S Blaum; Jess Tyrrell; Thomas A Jowitt; Simon J Clark; Edward Tarelli; Dusan Uhrín; Paul N Barlow; Robert B Sim; Anthony J Day; Susan M Lea Journal: J Exp Med Date: 2007-09-24 Impact factor: 14.307
Authors: Juan Liu; Purushottam Jha; Valeriy V Lyzogubov; Ruslana G Tytarenko; Nalini S Bora; Puran S Bora Journal: J Biol Chem Date: 2011-04-22 Impact factor: 5.157
Authors: Henry F Edelhauser; Cheryl L Rowe-Rendleman; Michael R Robinson; Daniel G Dawson; Gerald J Chader; Hans E Grossniklaus; Kay D Rittenhouse; Clive G Wilson; David A Weber; Baruch D Kuppermann; Karl G Csaky; Timothy W Olsen; Uday B Kompella; V Michael Holers; Gregory S Hageman; Brian C Gilger; Peter A Campochiaro; Scott M Whitcup; Wai T Wong Journal: Invest Ophthalmol Vis Sci Date: 2010-11 Impact factor: 4.799