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.
Rohrer
Bärbel
B
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, USA. rohrer@musc.edu
Long
Qin
Q
Coughlin
Beth
B
Renner
Brandon
B
Huang
Yuxiang
Y
Kunchithapautham
Kannan
K
Ferreira
Viviana P
VP
Pangburn
Michael K
MK
Gilkeson
Gary S
GS
Thurman
Joshua M
JM
Tomlinson
Stephen
S
Holers
V Michael
VM
D000818:Animals; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D008268:Macular Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D051056:Complement Inactivating Agents; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse