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Rajendra Kumar-Singh, Siobhan M Cashman; Rescue of Complement Mediated Pathology in a Murine Model of Macular Degeneration by Adenovirus-Mediated Delivery of the Alternative Pathway Regulator, Factor H. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1319.
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We have previously described a murine model of complement activation in the retina that recapitulates many of the features of age-related macular degeneration (AMD), including increased vascular permeability, endothelial cell proliferation, RPE cell atrophy and photoreceptor degeneration. This model manifests these features within 2 weeks of injection of an adenovirus expressing murine complement component 3 (AdcmvC3). In this study, we investigated the potential of factor H, a complement regulator strongly implicated in AMD, to attenuate the AdcmvC3-induced phenotype by co-injection of an adenovirus expressing factor H.
We constructed an adenovirus expressing murine factor H (AdCAGfH). Adult mice were co-injected with either AdcmvC3 and AdCAGfH or AdcmvC3 and and a control virus, AdcmvGFP, into the subretinal space. At 8 days post-injection, mice were analyzed by electroretinography. Eyes were harvested for analysis by histology and immunohistochemistry.
Mice co-injected with AdcmvC3 and AdCAGfH showed a 110% and 140% increase in A- and B-waves, respectively, relative to mice co-injected with AdcmvC3 and AdcmvGFP. While rescue of RPE cell phenotype was not complete, with persistent hypertrophy and hyperplasia observed in eyes injected with AdcmvC3 and AdCAGfH, a significant 125% reduction in RPE cell atrophy was observed relative to control eyes. While complete loss of outer segments occurred in >50% of the lesion in control eyes, <10% of the lesion in eyes co-injected with AdcmvC3 and AdCAGfH had complete outer segment loss. Staining for endothelial cells, using Griffonia Simplificolia Lectin I (GSL I), indicated a 275% reduction in GSL I staining in eyes injected with AdcmvC3 and AdCAGfH relative to control-injected eyes.
The AdcmvC3-induced features of a murine model of complement activation in the retina can be attenuated by adenovirus-mediated delivery of the alternative complement pathway regulator, factor H. This model will be useful in investigating the potential of other anti-complement therapies for treatment of AMD and other complement-mediated diseases of the retina.
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