title: A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurosciences, Division of Research, Medical University of South Carolina, Charleston, South Carolina 29425, USA. rohrer@musc.edu
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
authors.forename: Qin
authors.initials: Q
authors.lastname: Long
authors.forename: Beth
authors.initials: B
authors.lastname: Coughlin
authors.forename: R Brooks
authors.initials: RB
authors.lastname: Wilson
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Huang
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Peter H
authors.initials: PH
authors.lastname: Tang
authors.forename: Kannan
authors.initials: K
authors.lastname: Kunchithapautham
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000503:physiopathology; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000235:genetics; D017242:Complement Factor H / Q000037:antagonists & inhibitors; D003170:Complement Pathway, Alternative / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007262:Infusions, Intravenous; D008268:Macular Degeneration / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012160:Retina / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017242:Complement Factor H