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Maria Avrutsky, Ying Y Jean, Alexandra J White, Scott Snipas, Guy Salvesen, Carol Troy; Caspase-9 Inhibitor Eyedrops Reduce Edema and Protect Retinal Function Following Central Retinal Vein Occlusion. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1537.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal edema is a complication of diabetes and retinal vein occlusion, resulting when damaged vessels leak fluid into the retina. Without timely intervention, edema can lead to death of retinal neurons, causing permanent vision loss. Despite available therapies, many patients do not respond to treatment. We characterized the retinal changes caused by a laser photocoagulation model of central retinal vein occlusion (CRVO), and identified that caspase-9 activity plays an essential role in edema formation. We developed a highly specific caspase-9 inhibitor which can be administered using topical eyedrops to test a potential new treatment for retinal edema and CRVO.
CRVO was achieved in 2-4 month-old C57Bl/6J mice by tail-vein injection of rose bengal, followed by laser photocoagulation of retinal veins. In vivo analyses – optical coherence tomography (OCT), focal electroretinogram (ERG) and fluorescein angiography - were conducted with the Micron IV system (Phoenix Research Labs). Mice received eyedrops containing 10μg caspase-9 inhibitor peptide or vehicle alone, immediately following CRVO.
CRVO induced acute edema followed by retinal thinning. Affected eyes developed clinical features of retinal vein occlusion, including retinal hemorrhages, edema, dilation of retinal veins, retinal detachment and cotton wool spots. Fluorescein angiography revealed leakage in areas affected by edema. We used OCT to measure the morphological changes to specific retinal layers at different time points following CRVO. Caspase-9 and VEGF levels increased after injury, as measured by western blot and immunohistochemistry. We demonstrate effective retinal uptake of our caspase-9 inhibitor peptide following administration of topical eyedrops. Mice which received treatment with inhibitor eyedrops immediately following CRVO, developed less overall edema (P<0.05), protected the inner retinal layers from thinning (P<0.05) and had improved retinal function via ERG (P<0.05)
Caspase-9 activity in the retina contributes to the disruption of retinal morphology and subsequent retinal dysfunction following CRVO. We developed an inhibitor peptide which is exquisitely specific for caspase-9 activity, and which can be delivered to the retina via topical eyedrops. Treatment with the inhibitor immediately following CRVO confers both morphological and functional retinal protection.
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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