A Targeted Inhibitor of the Complement Alternative Pathway Reduces RPE Injury and Angiogenesis in Models of Age-Related Macular Degeneration
Genetic variations in complement factor H (fH), an inhibitor of the complement alternative pathway (CAP), and oxidative stress are associated with age-related macular degeneration (AMD). Recently, novel complement therapeutics have been created with the capacity to be “targeted” to sites of complement activation. One example is our recombinant form of fH, CR2-fH, which consists of the N-terminus of mouse fH that contains the CAP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. CR2-fH was investigated in vivo in the mouse model of choroidal neovascularization (CNV) and in vitro in oxidatively stressed RPE cell monolayers. RPE deterioration and CNV development were found to require CAP activation, and specific CAP inhibition by CR2-fH reduced the loss of RPE integrity and angiogenesis in CNV. In both the in vivo and in vitro paradigm of RPE damage, a model requiring molecular events known to be involved in AMD, complement-dependent VEGF production, was confirmed. These data may open new avenues for AMD treatment strategies.
KeywordsMembrane Attack Complex Complement Alternative Pathway VEGF Secretion Complement Alternative Pathway Activation Membrane Attack Complex Deposition
This work was supported in part by National Institutes of Health Grants DK077661 and DK076690 (J.M.T.), DK035081 (M.K.P.), EY13520 and EY017465 (B.R.) and HL082485 (S.T.), a vision core grant (EY014793), the Foundation Fighting Blindness, American Heart Association grant 0735101N (V.P.F.), and an unrestricted grant to MUSC from Research to Prevent Blindness (RPB), Inc., New York, NY. Animal studies were conducted in a facility constructed with support from the NIH (C06 RR015455). B.R. is a RPB Olga Keith Weiss Scholar.
We acknowledge Drs. Helga Sandoval and Luis Fernandez de Castro from the McGill Laser Center at MUSC for training us in the use of the Argon Laser, Efrain Martinez for producing CR2-fH, and Luanna Bartholomew for critical review.
The authors declare the following disclosures. V.M.H. is a co-founder of Taligen Therapeutics, Inc., which develops complement inhibitors for therapeutic use; S.T., G.S.G., J.M.T. and B.R. are consultants to Taligen Therapeutics. M.K.P. is an officer of, and has a financial interest in Complement Technology, a supplier of complement reagents.
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