Systemic Human CR2-Targeted Complement Alternative Pathway Inhibitor Ameliorates Mouse Laser-Induced Choroidal Neovascularization
| العنوان: | Systemic Human CR2-Targeted Complement Alternative Pathway Inhibitor Ameliorates Mouse Laser-Induced Choroidal Neovascularization |
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| المؤلفون: | Beth Coughlin, Mausumi Bandyopadhyay, Bärbel Rohrer, V. Michael Holers |
| المصدر: | Journal of Ocular Pharmacology and Therapeutics. 28:402-409 |
| بيانات النشر: | Mary Ann Liebert Inc, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Vascular Endothelial Growth Factor A, genetic structures, Recombinant Fusion Proteins, Complement Pathway, Alternative, Angiogenesis Inhibitors, Biology, Ligands, Real-Time Polymerase Chain Reaction, Mice, Complement inhibitor, Electroretinography, medicine, Animals, Humans, Pharmacology (medical), RNA, Messenger, Receptor, Pharmacology, Lasers, Original Articles, Macular degeneration, medicine.disease, Immunohistochemistry, Choroidal Neovascularization, eye diseases, Complement system, Mice, Inbred C57BL, Ophthalmology, Vascular endothelial growth factor A, Choroidal neovascularization, Complement Factor H, Factor H, Immunology, Cancer research, Alternative complement pathway, Receptors, Complement 3d, sense organs, medicine.symptom, Biomarkers, Plasmids |
| الوصف: | Genetic associations and the presence of complement components within pathological structures of age-related macular degeneration (AMD) have generated the hypothesis that AMD is caused by chronic local complement activation. Since the majority of activity in the common terminal pathway results from engagement of the amplification loop, the alternative pathway has been proposed as a logical therapeutic target. We recently generated a factor H (fH)-based complement inhibitor (CR2-fH) with the capacity to be "targeted" to sites of complement C3 activation. We asked whether the human therapeutic (TT30) is effective in a mouse model of AMD.Choroidal neovascularization (CNV) was induced by argon laser photocoagulation of Bruch's membrane. Every other day, mice received intravenous injections of TT30 or vehicles, and after 6 days, the presence or absence of CNV and CNV-related changes were evaluated. Area of CNV, photoreceptor cell function, gene expression for complement components and cytokines, vascular endothelial growth factor (VEGF) protein levels, and TT30 bioavailability were determined.CNV development, which has previously been shown to require local complement activation, could be reduced by intravenous TT30 delivery. Specific inhibition of the alternative pathway not only reduced angiogenesis in CNV, but also ameliorated changes in several associated disease-related biomarkers, including diminished retinal function and molecular events known to be involved in AMD such as VEGF production. After intravenous injection, TT30 localized to CNV lesion sites in the retinal pigmented epithelium-choroid.Systemic administration of TT30 was found to reduce CNV pathology. These data may open new avenues for novel systemic AMD treatment strategies. |
| تدمد: | 1557-7732 1080-7683 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a36c330f00193c2382bc9921a6ff31b3Test https://doi.org/10.1089/jop.2011.0212Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a36c330f00193c2382bc9921a6ff31b3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15577732 10807683 |
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