Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1

J. Shen; R. Samul; R. L. Silva; H. Akiyama; H. Liu; Y. Saishin; S. F. Hackett; S. Zinnen; K. Kossen; K. Fosnaugh; C. Vargeese; A. Gomez; K. Bouhana; R. Aitchison; P. Pavco; P. A. Campochiaro

doi:10.1038/sj.gt.3302641

Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1

J. Shen, R. Samul, R. L. Silva, H. Akiyama, H. Liu, Y. Saishin, S. F. Hackett, S. Zinnen, K. Kossen, K. Fosnaugh, C. Vargeese, A. Gomez, K. Bouhana, R. Aitchison, P. Pavco, P. A. Campochiaro

School of Medicine

Research output: Contribution to journal › Article › peer-review

282 Scopus citations

Abstract

In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0μg of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0μg of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential.

Original language	English (US)
Pages (from-to)	225-234
Number of pages	10
Journal	Gene Therapy
Volume	13
Issue number	3
DOIs	https://doi.org/10.1038/sj.gt.3302641
State	Published - Feb 2006

Keywords

Age-related macular degeneration
Angiogenesis
Choroidal neovascularization
Diabetic retinopathy
Ischemic retinopathy
Retinal neovascularization
Small interfering RNA

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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10.1038/sj.gt.3302641

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@article{a0448699326642a287e8056ca8f28c2d,

title = "Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1",

abstract = "In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0μg of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0μg of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential.",

keywords = "Age-related macular degeneration, Angiogenesis, Choroidal neovascularization, Diabetic retinopathy, Ischemic retinopathy, Retinal neovascularization, Small interfering RNA",

author = "J. Shen and R. Samul and Silva, {R. L.} and H. Akiyama and H. Liu and Y. Saishin and Hackett, {S. F.} and S. Zinnen and K. Kossen and K. Fosnaugh and C. Vargeese and A. Gomez and K. Bouhana and R. Aitchison and P. Pavco and Campochiaro, {P. A.}",

note = "Funding Information: This work was supported by a grant from Sirna Therapeutics, Inc. PAC is the George S and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience. PAC is a consultant for Sirna Therapeutics, Inc., which is monitored by the Conflict of Interest Committee of the Johns Hopkins University School of Medicine.",

year = "2006",

month = feb,

doi = "10.1038/sj.gt.3302641",

language = "English (US)",

volume = "13",

pages = "225--234",

journal = "Gene Therapy",

issn = "0969-7128",

publisher = "Nature Publishing Group",

number = "3",

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TY - JOUR

T1 - Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1

AU - Shen, J.

AU - Samul, R.

AU - Silva, R. L.

AU - Akiyama, H.

AU - Liu, H.

AU - Saishin, Y.

AU - Hackett, S. F.

AU - Zinnen, S.

AU - Kossen, K.

AU - Fosnaugh, K.

AU - Vargeese, C.

AU - Gomez, A.

AU - Bouhana, K.

AU - Aitchison, R.

AU - Pavco, P.

AU - Campochiaro, P. A.

N1 - Funding Information: This work was supported by a grant from Sirna Therapeutics, Inc. PAC is the George S and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience. PAC is a consultant for Sirna Therapeutics, Inc., which is monitored by the Conflict of Interest Committee of the Johns Hopkins University School of Medicine.

PY - 2006/2

Y1 - 2006/2

N2 - In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0μg of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0μg of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential.

AB - In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0μg of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0μg of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential.

KW - Age-related macular degeneration

KW - Angiogenesis

KW - Choroidal neovascularization

KW - Diabetic retinopathy

KW - Ischemic retinopathy

KW - Retinal neovascularization

KW - Small interfering RNA

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U2 - 10.1038/sj.gt.3302641

DO - 10.1038/sj.gt.3302641

M3 - Article

C2 - 16195704

AN - SCOPUS:31444440290

SN - 0969-7128

VL - 13

SP - 225

EP - 234

JO - Gene Therapy

JF - Gene Therapy

IS - 3

ER -

Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1

Abstract

Keywords

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