Ocular neuroprotection by siRNA targeting caspase-2 |
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| Authors: | Z Ahmed H Kalinski M Berry M Almasieh H Ashush N Slager A Brafman I Spivak N Prasad I Mett E Shalom E Alpert A Di Polo E Feinstein A Logan |
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| Institution: | 1Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK;2Neuregenix Ltd, The Research Park, Birmingham, UK;3Quark Pharmaceuticals Inc. (Research Division), Weizmann Science Park, Ness Ziona, Israel;4Department of Pathology and Cellular Biology, University of Montreal, Montreal, Quebec, Canada |
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| Abstract: | Retinal ganglion cell (RGC) loss after optic nerve damage is a hallmark of certain human ophthalmic diseases including ischemic optic neuropathy (ION) and glaucoma. In a rat model of optic nerve transection, in which 80% of RGCs are eliminated within 14 days, caspase-2 was found to be expressed and cleaved (activated) predominantly in RGC. Inhibition of caspase-2 expression by a chemically modified synthetic short interfering ribonucleic acid (siRNA) delivered by intravitreal administration significantly enhanced RGC survival over a period of at least 30 days. This exogenously delivered siRNA could be found in RGC and other types of retinal cells, persisted inside the retina for at least 1 month and mediated sequence-specific RNA interference without inducing an interferon response. Our results indicate that RGC apoptosis induced by optic nerve injury involves activation of caspase-2, and that synthetic siRNAs designed to inhibit expression of caspase-2 represent potential neuroprotective agents for intervention in human diseases involving RGC loss. |
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| Keywords: | synthetic siRNA retinal ganglion cells apoptosis caspase-2 neuroprotection |
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