title: Ocular neuroprotection by siRNA targeting caspase-2.
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.
authors.affiliation: Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. z.ahmed.1@bham.ac.uk
authors.forename: Z
authors.initials: Z
authors.lastname: Ahmed
authors.forename: H
authors.initials: H
authors.lastname: Kalinski
authors.forename: M
authors.initials: M
authors.lastname: Berry
authors.forename: M
authors.initials: M
authors.lastname: Almasieh
authors.forename: H
authors.initials: H
authors.lastname: Ashush
authors.forename: N
authors.initials: N
authors.lastname: Slager
authors.forename: A
authors.initials: A
authors.lastname: Brafman
authors.forename: I
authors.initials: I
authors.lastname: Spivak
authors.forename: N
authors.initials: N
authors.lastname: Prasad
authors.forename: I
authors.initials: I
authors.lastname: Mett
authors.forename: E
authors.initials: E
authors.lastname: Shalom
authors.forename: E
authors.initials: E
authors.lastname: Alpert
authors.forename: A
authors.initials: A
authors.lastname: Di Polo
authors.forename: E
authors.initials: E
authors.lastname: Feinstein
authors.forename: A
authors.initials: A
authors.lastname: Logan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053143:Caspase 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005901:Glaucoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents; D009900:Optic Nerve / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D053143:Caspase 2