Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF‐1α and VEGF

Jiang, Jian; Xia, Xiaobo; Xu, Huizhuo; Xiong, Ye; Song, Wook; Xiong, Siqi; Li, Yan

doi:10.1002/jcp.21566

Cited by 65 publications

(41 citation statements)

References 28 publications

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“…It has been reported that the silencing of HIF-1α is effective at inhibiting retinal neovascularization in experimental mice models (Jiang et al, 2009).…”

Section: Diabetic Retinopathymentioning

confidence: 99%

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Guzmán-Aránguez

Loma

Pintor

2013

British J Pharmacology

109

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RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments. AbbreviationsAMD, age-related macular degeneration; Apaf-1, apoptotic protease-activating factor-1; CNV, choroidal neovascularization; CTGF, connective tissue growth factor; DR, diabetic retinopathy; dsRNA, double-stranded RNA; ECM, extracellular matrix; HIF-1α, hypoxia-inducible factor-1α; IOP, intraocular pressure; ONC, optic nerve crush; POAG, open-angle glaucoma; RGC, retinal ganglion cell; RISC, RNA-induced silencing complex; RNAi, RNA interference; RP, retinitis pigmentosa; Smad, signalling mathers against decapentaplegic; SPARC, secreted protein acidic and rich in cysteine; TLR3, toll-like receptor 3; TM, trabecular meshwork; TXNIP, thioredoxin interacting protein IntroductionRNA interference (RNAi) technology has been used to elucidate gene function, to generate model systems and to identify new molecular targets. In addition, RNAi is currently progressing from basic research to potential therapeutic applications. Because any gene that causes or contributes to a disease is susceptible to suppression by RNAi, RNAi therapy represents a promising biomedical strategy for treating a diverse range of diseases including cancer, cardiovascular diseases, neurodegenerative diseases, inflammatory conditions, viral infections and ocular diseases (Guo et al., 2010). In particular, the accessibility of the eye facilitates small-interfering RNA (siRNA) delivery, and naked siRNA has been efficiently applied by topical administration to the anterior segment or by intravitreal injection to the posterior segment (de Fougerolles, 2008). As the localized delivery of siRNA to the eye is less challenging than for other tissues, there has been significant progress made towards its use as a therapeutic procedure for eye diseases. In fact, several siRNA-based therapeutic agents for o...

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“…It has been reported that the silencing of HIF-1α is effective at inhibiting retinal neovascularization in experimental mice models (Jiang et al, 2009).…”

Section: Diabetic Retinopathymentioning

confidence: 99%

Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Guzmán-Aránguez

Loma

Pintor

2013

British J Pharmacology

109

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“…OIR mice were anesthetized intraperitoneally with 1% pentobarbital sodium (30 mg/kg body weight) and given an intravitreal injection of recombinant PGC-1α or PBS. The tip of a 10 mm 34-gauge steel needle, mounted on a 5 µl Hamilton syringe, was pushed through the sclera, 1 mm posterior to the corneoscleral limbus, into the vitreous body (18). OIR mice received an intravitreal injection of 1 µl (0.25 µg/µl) recombinant PGC-1α (OIR PGC-1α group) or 1 µl PBS (OIR control group) at P11, and were returned to room air at P12.…”

Section: Measurement Of Vegf Protein Expression In Hrvecs Usingmentioning

confidence: 99%

Application of recombinant peroxisome proliferator-activated receptor-γ coactivator-1α mediates neovascularization in the retina

Jiang

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is able to induce the expression of vascular endothelial growth factor (VEGF), promoting the formation of new blood vessels in skeletal muscle. The aim of the current study was to determine whether PGC-1α is able to regulate angiogenesis in human retinal vascular endothelial cells (hRVECs) in vitro and in retinas in vivo. hRVECs treated with recombinant PGC-1α were incubated for 24 h and then placed into a normoxic (20% O 2 ) or hypoxic (1% O 2 ) environment for a further 16 h. Following this, VEGF mRNA and protein levels were significantly increased. Cellular proliferation was enhanced by treatment with recombinant PGC-1α in normoxic and hypoxic conditions. At 24 h following recombinant PGC-1α treatment, hRVECs were plated into Matrigel-coated plates and cultured under normoxic (20% O 2 ) or hypoxic (1% O 2 ) conditions for a further 24 h. Recombinant PGC-1α-treated cells were observed to form significantly greater numbers of tubes. In a C57BL/6J mouse model of ischemic retinopathy, mice received an intravitreal injection of recombinant PGC-1α, resulting in a significant increase in VEGF mRNA and protein levels in the retina. Retinal neovascular tufts and neovascular nuclei were investigated by angiographic and cross-sectional analysis and were observed to be significantly increased in the PGC-1α group compared with the control group. These results indicate that PGC-1α is able to induce angiogenesis in hRVECs and retinas, and suggests that PGC-1α is a potential anti-angiogenic target in retinal neovascularization.

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“…The silencing of hypoxia inducible factor-1alpha (HIF-1alpha), that regulates the VEGF expression in hypoxic conditions of ocular angiogenesis is also under investigation to treat CNV (93). siRNA targeting the TGF-β, involved in fibrotic scars, seems to be another great potential to treat AMD (94).…”

Section: Small Interference Rna (Sirna)mentioning

confidence: 99%