Ocular neuroprotection by siRNA targeting caspase-2

Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Cell Death & Disease (Impact Factor: 5.01). 06/2011; 2(6):e173. DOI: 10.1038/cddis.2011.54
Source: PubMed


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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Available from: Zubair Ahmed
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    • "The most advanced programs for ocular indications are Quark's QPI-007 designed to silence Caspase 2, currently in Phase II/III for the treatment of Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) and Sylentis' bamosiran (SYL040012), targeting β2-Adrenergic Receptor (ADRB2) for the treatment of glaucoma, in phase IIb. QPI- 1007 is a 19-nt modified siRNA that has shown to be safe when injected intravitreally (IVT) to animal models and humans (Ahmed et al., 2011; Solano et al., 2014). The compound is currently being investigated in a phase II/III trial to analyze whether multiple IVT doses of this compound are able to improve visual acuity in patients suffering NAION. "
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    • "In further experiments, 5 mM of Pen1 or Pen1-C6DN was injected. Intravitreal injections were repeated every 7 days based on previous experiments with other caspase inhibitors (Ahmed et al., 2011). Twenty micrograms per eye of siCASP2 was injected along with either 5 mM Pen1 or Pen1-C6DN. "
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    • "If an AMPAR lacks a GluA2 subunit, then it will be permeable to Ca2+. The presence of a GluA2 subunit will almost always render the channel impermeable to Ca2+ [8]. This is determined by post- transcriptional modification-RNA editing of the Q/R editing site of the GluA2 mRNA. "
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