Eliminating Alternative Complement Pathway Signaling Reduces CNV in a Mouse Model of Wet AMD

Abstract

Purpose: : Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. There is evidence that the complement system plays a significant role in the pathogenesis of AMD, and polymorphisms interfering with the function of factor H, an inhibitor of the alternative pathway of complement activation, are associated with increased risk of AMD. Here we characterize a novel inhibitor of the alternative complement pathway that is targeted to the site of complement activation in a model of AMD and assess its efficacy at reducing choroidal neovascularization (CNV). The inhibitor is a fusion protein consisting of a complement receptor 2 fragment linked to a complement inhibitory domain of factor H (CR2-FH).

Methods: : CNV progression was analyzed in C57BL/6 mice using molecular, histological and electrophysiological readouts. The effects of CR2-FH were compared for intravenous or intraocular injections, using the complement factor B knockout mouse (CFB^-/-) as a positive control.

Results: : Argon laser photocoagulation reliably induced CNV, leading to a time-dependent increase in CNV lesions, concomitant with increased mRNA for complement factor C3 and VEGF and with deposition of C3d in the lesion. Mice without a functional alternative complement pathway (CFB^-/-) had reduced CNV progression, preserved ERG amplitudes and a blunted increase in marker gene expression. The alternative pathway inhibitor CR2-FH significantly reduced CNV based on the same readouts, regardless of whether CR2-FH was administered intravenously or intraocularly. Bioavailability studies showed targeting of CR2-FH after intravenous administration to the lesion sites.

Conclusions: : The data show that the alternative complement pathway plays an important role in CNV development and demonstrate that specific inhibition of the alternative pathway represents a potential treatment for AMD. Importantly, CR2-FH targets to ocular tissues and provides protection from the development of CNV following intravenous injection, a finding that opens a new avenue for the development of treatment strategies for AMD.

Keywords: age-related macular degeneration • choroid: neovascularization • protective mechanisms