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: 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
• Journal: Cell death & disease (Cell Death Dis) Vol. 2 Pg. e173 (Jun 16 2011) ISSN: 2041-4889 [Electronic] England
• PMID: 21677688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• RNA, Small Interfering
• Caspase 2

Topics

• Animals
• Apoptosis (genetics)
• Caspase 2 (biosynthesis, deficiency, genetics, metabolism)
• Cytoprotection (genetics)
• Disease Models, Animal
• Female
• Glaucoma (enzymology, genetics, pathology, prevention & control)
• Neuroprotective Agents
• Optic Nerve (enzymology, metabolism, pathology)
• RNA, Small Interfering (genetics)
• Rats
• Rats, Wistar
• Retinal Ganglion Cells (cytology, metabolism)
• Structure-Activity Relationship