Ocular neuroprotection by siRNA targeting caspase-2

Zubair Ahmed; H Kalinski; Martin Berry; M Almasieh; H Ashush; N Slager; A Brafman; I Spivak; N Prasad; I Mett; E Shalom; E Alpert; A Di Polo; E Feinstein; Ann Logan

doi:10.1038/cddis.2011.54

Ocular neuroprotection by siRNA targeting caspase-2

Zubair Ahmed, H Kalinski, Martin Berry, M Almasieh, H Ashush, N Slager, A Brafman, I Spivak, N Prasad, I Mett, E Shalom, E Alpert, A Di Polo, E Feinstein, Ann Logan

Birmingham Medical School

Research output: Contribution to journal › Article

92 Citations (Scopus)

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.

Original language	English
Pages (from-to)	e173
Journal	Cell death & disease
Volume	2
Early online date	16 Jun 2011
DOIs	https://doi.org/10.1038/cddis.2011.54
Publication status	Published - 16 Jun 2011

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10.1038/cddis.2011.54

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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.",

author = "Zubair Ahmed and H Kalinski and Martin Berry and M Almasieh and H Ashush and N Slager and A Brafman and I Spivak and N Prasad and I Mett and E Shalom and E Alpert and {Di Polo}, A and E Feinstein and Ann Logan",

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T1 - Ocular neuroprotection by siRNA targeting caspase-2

AU - Ahmed, Zubair

AU - Kalinski, H

AU - Berry, Martin

AU - Almasieh, M

AU - Ashush, H

AU - Slager, N

AU - Brafman, A

AU - Spivak, I

AU - Prasad, N

AU - Mett, I

AU - Shalom, E

AU - Alpert, E

AU - Di Polo, A

AU - Feinstein, E

AU - Logan, Ann

PY - 2011/6/16

Y1 - 2011/6/16

N2 - 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.

AB - 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.

U2 - 10.1038/cddis.2011.54

DO - 10.1038/cddis.2011.54

M3 - Article

C2 - 21677688

SN - 2041-4889

VL - 2

SP - e173

JO - Cell death & disease

JF - Cell death & disease

ER -

Ocular neuroprotection by siRNA targeting caspase-2

Abstract

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