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Baerbel Rohrer, Gloriane Schnabolk, Balasubramaniam Annamalai, Nathaniel Parsons, Elisabeth Obert, Alfred S Lewin, Stephen Tomlinson; Delivery of CR2-fH using AAV vector therapy as a treatment strategy in mouse model of choroidal neovascularization.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3388.
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© ARVO (1962-2015); The Authors (2016-present)
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 (AP) of complement, are associated with increased risk of AMD. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to a complement inhibitory domain of factor H (CR2-fH) as an efficacious treatment of choroidal neovascularization (CNV) when delivered intravenously. Here we test AAV as an alternative ocular delivery systems for CR2-fH.
AAV vectors (AAV5-VMD2-CR2-fH and AAV5-VMD2-mCherry) were injected subretinally; and retinal reattachment monitored by fundus photography, optical coherence tomography (OCT) and electroretinography. CNV was induced using argon laser photocoagulation after 1 month, and progression analyzed in C57BL/6J mice using OCT. Bioavailability of CR2-fH was evaluated by dot blot analysis and efficacy as an AP inhibitor was confirmed by C3a ELISA, both using RPE/choroid samples.
Apical and basal secretion of CR2-fH was confirmed in polarized RPE cells. A safe concentration of AAV5-VMD2-CR2-fH was identified. Lack of antibody production against CR2-fH was confirmed. CR2-fH delivered via AAV5-mediated expression significantly reduced CNV when compared to mCherry. Bioavailability studies showed that this treatments route delivered CR2-fH to the RPE/choroid at similar levels when compared to intravenous administration, and resulted in a reduction of CNV-mediated C3a production.
The results add to the existing data that the AP of complement plays an important role in CNV development and demonstrate that specific inhibition of the AP represents a potential treatment for AMD. Importantly, demonstration of efficacy using this long-term AAV-based treatment strategy opens up new avenues for the development of treatment strategies for AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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