Ocular neuroprotection by siRNA targeting caspase-2

Cell Death Dis. 2011 Jun 16:2:e173. doi: 10.1038/cddis.2011.54.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Neuroprotective Agents
  • RNA, Small Interfering
  • Caspase 2