A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration
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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.
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Several experiments using mouse models of laser-induced CNV have demonstrated that all complement pathways, particularly the alternative and terminal pathways, play a significant role in angiogenesis.
“Several experiments using mouse models of laser-induced CNV have demonstrated that all complement pathways, particularly the alternative and terminal pathways, play a significant role in angiogenesis [150,152,153,154,155,156,157,158,159,160,161,162,163].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [160]
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- Authors
- Rohrer, B., Long, Q., Coughlin, B., Wilson, R. B., Huang, Y., Qiao, F., Tang, P. H., Kunchithapautham, K., Gilkeson, G. S., & Tomlinson, S.
- Affiliations
- From the Departments of Neurosciences/Division of Research,2Ophthalmology,
- From the Departments of Neurosciences/Division of Research,
- Microbiology and Immunology, and
- Ophthalmology,
- Medical University of South Carolina (US)
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2009-07-01
- Volume
- 50
- Issue
- 7
- Pages
- 3056
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC2908507
- OpenAlex
- W2025576158
- Cited by
- 154
- References
- 39
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 2 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 15 · 2014: 12 · 2013: 11 · 2012: 21
- FWCI
- 18.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1c06rr015455-01a1)
- National Heart, Lung, and Blood Institute (HL86576, R01HL086576)
- National Eye Institute (R24EY014793, EY013520, R43EY017465, EY017465, R01EY013520)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, alternative complement pathway, complement factor H, CR2, choroidal neovascularization, angiogenesis inhibition, C3 deposition, vascular endothelial growth factor, laser-induced CNV
- MeSH terms
- Animals, Choroid, Complement Activation, Complement Pathway, Alternative, Complement C3, Disease Models, Animal, Electroretinography, Female, Infusions, Intravenous, Macular Degeneration, Male, Mice, Inbred C57BL, Recombinant Fusion Proteins, Retina, RNA, Messenger, Up-Regulation, Complement Factor H, Mice, Knockout, Fluorescent Antibody Technique, Indirect, Reverse Transcriptase Polymerase Chain Reaction, Choroidal Neovascularization, Vascular Endothelial Growth Factor A, Mice, Retinal Pigment Epithelium
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