In vivo use of oligonucleotides to inhibit choroidal neovascularisation in the eye

Garrett, Kerryn L.; Shen, Weiyong; Rakoczy, P. Elizabeth

doi:10.1002/jgm.197

Cited by 43 publications

(27 citation statements)

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“…It is assumed that DS135 binds to the IRES sequence and prevents the complex folding patterns required for efficient ribosome entry (Huez et al, 1998), therefore preventing translation of up-regulated VEGF mRNA. In our own hands, the ability of DS135 to down-regulate VEGF has been demonstrated by Western analysis, ELISA, and quantitative Taqman RT-PCR techniques using the D407 RPE cell line before the efficacy study in the monkey (Garrett et al, 2001). By semiquantified Western blot analysis, DS135 showed a dose-dependent inhibition of VEGF protein production, with 66% and 93% reduction of VEGF levels when treated with 1.0 and 5.0 M DS135 in vitro.…”

Section: Shen Et Almentioning

confidence: 97%

“…Our preliminary experiments have shown successful uptake and persistence of PSoligos in the retina after intravitreal (IV) injection (Rakoczy et al, 1996;Shen et al, 1999). Recently, a series of sequences of the VEGF gene were assessed in an in vitro screening system, and a PS-oligo targeting both human and rat VEGF 165 genes upstream of the translation initiation code, named DS135 in this project, was selected (Garrett et al, 2001). This PS-oligo has been demonstrated to suppress 35% levels of VEGF production under hypoxic condition in vitro and inhibit a laser-induced CNV via IV injection in the rat (Garrett et al, 2001).…”

mentioning

confidence: 99%

“…Recently, a series of sequences of the VEGF gene were assessed in an in vitro screening system, and a PS-oligo targeting both human and rat VEGF 165 genes upstream of the translation initiation code, named DS135 in this project, was selected (Garrett et al, 2001). This PS-oligo has been demonstrated to suppress 35% levels of VEGF production under hypoxic condition in vitro and inhibit a laser-induced CNV via IV injection in the rat (Garrett et al, 2001). In this article, we provide further preclinical information on DS135 using the rhesus monkey, aiming to evaluate its intraocular safety and biologic efficacy in human-like retina, with a further direction to achieve therapeutic inhibition of CNV in humans.…”

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confidence: 99%

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Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Shen

Garrett

Wang

et al. 2002

Laboratory Investigation

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SUMMARY:Overexpression of vascular endothelial growth factor (VEGF) has been strongly implicated in the development of choroidal neovascularization (CNV) in patients with age-related macular degeneration. In this study, a phosphorothioate oligonucleotide (PS-oligo) targeting both human and rat VEGF 165 genes upstream of the translation initiation code, named DS135 in this study, was evaluated for its uptake dynamics and retinal tolerance after intravitreal (IV) and subretinal (SR) injections in the rhesus monkey. Intravitreal and SR injections of a fluorescent-labeled DS135 (FL-DS135) resulted in both dose-and time-dependent uptake and persistence, and FL-DS135 remained detectable in the retina for at least 3 weeks after injection. Ophthalmic examination showed transient vitreous haze after IV delivery of a high dose but not with a low dose of FL-DS135. Histologic examination showed no evidence of retinal degeneration with respect to IV delivery. After SR delivery, however, dose-related cellular infiltration, transient residual fluid, and slight distortion of the neuroretina were observed. The biologic efficacy of DS135 was further assessed in a laser-induced CNV model, and development of CNV was determined by fluorescein angiography and histologic examination. Incomplete inhibition of CNV formation was observed after IV and SR injection of DS135, but no statistically significant difference was achieved when compared with dose-matched control of PS-oligo. Analysis of fluorescein angiogram and histologic examination showed less than 30% incidence of CNV development in this monkey model. Our study demonstrated that PS-oligos can be successfully introduced into the retina, although with potential limitations, after SR delivery. DS135, a PS-oligo targeting the VEGF gene upstream of the translation initiation code, partially inhibited CNV formation. An improved CNV model is necessary for further confirmation of the full therapeutic potency of DS135 before clinical application. (Lab Invest 2002, 82:167-182).

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Section: Shen Et Almentioning

confidence: 97%

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confidence: 99%

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Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Shen

Garrett

Wang

et al. 2002

Laboratory Investigation

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“…der la ser in du zier ten re tina len Neo vas ku lari sie rung in Rat ten, wur de eine re du zierte Ge fäß neu bil dung über meh re re Wochen durch in tra vi trea le Ap pli ka ti on eines VEGF-spe zi fi schen "An ti sen se"-ON er reicht [10].…”

Section: Ral and Non VI Ral Gene Ther A Py For Treat Ment Of Ret Iunclassified

Virale und nichtvirale Gentherapieansätze zur Behandlung von Netzhauterkrankungen

2005

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Die Ent wick lung und Um set zung von Gen the ra pie stra te gi en zur Hei lung von Netz hau ter kran kun gen er for dert die In te gra ti on ei ner Viel zahl von Fakto ren. Al len Stra te gi en ge mein sam ist die Be ein flus sung des Krank heits verlaufs auf der Ebe ne der Gene oder ihrer Tran skrip te. Ei ni ge ver fol gen hierbei die ge ziel te Ma ni pu la ti on des defek ten Gens, wäh rend an de re über se kun däre Ef fek to ren in die Me chanis men der Pa tho ge ne se ein grei fen. Die Be hand lung do mi nan ter Gen defek te er for dert meist die Ent fer nung des to xi schen Gen pro dukts, wo gegen bei re zes siv ver erb ten Krank heiten das de fek te Gen er setzt wird. In die sem Zu sam men hang er mög lich te erst die Iden ti fi zie rung von Mu ta tionen in zahl rei chen Ge nen die Ent wicklung von gen the ra peu ti schen Stra tegi en zur Hei lung von Netz hau ter krankun gen. Im Fol gen den möch ten wir ei ni ge erfolg rei che Stra te gi en zur Be hand lung von Neo vas ku la ri sie rungs de fek ten und Netz haut de ge ne ra tio nen dis kutie ren.

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“…We subsequently tested the efficacy of ODN-1 in reducing the extent of laser photocoagulation induced choroidal neovascularisation (CNV) in a rodent model. 11 However, like most other genetic-based therapies, delivery and longevity of the effects remain a limiting factor. More recently, we described the synthesis and use of lipophilic amino-acid dendrimers that enhanced the delivery of ODN-1 into the retinal tissue of rats.…”

Section: Introductionmentioning

confidence: 99%

Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

et al. 2005

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We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (Po0.05) the development of CNV for 4-6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P40.05) in mean severity score at 2 months (2.8670.09), 4 months (2.1570.17) or 6 months (2.770.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases. Gene Therapy (2005) 12, 1544-1550.

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In vivo use of oligonucleotides to inhibit choroidal neovascularisation in the eye

Cited by 43 publications

References 28 publications

Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Preclinical Evaluation of a Phosphorothioate Oligonucleotide in the Retina of Rhesus Monkey

Virale und nichtvirale Gentherapieansätze zur Behandlung von Netzhauterkrankungen

Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

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