Pegaptanib for Neovascular Age-Related Macular Degeneration

Gragoudas, Evangelos S.; Adamis, Anthony P.; Cunningham, Emmett T.; Feinsod, Matthew; Guyer, David R.

doi:10.1056/nejmoa042760

Cited by 2,095 publications

(963 citation statements)

References 23 publications

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“…Bevacizumab, which is approved for the treatment of colon cancer but not for the treatment of AMD, is closely related to ranibizumab. In contrast to pegaptanib that binds only the VEGF isoforms that are 165 kD (VEGF165) and larger [26], both ranibizumab and bevacizumab bind and inhibit all biologically active forms of VEGF [47]. Bevacizumab is a fulllength, humanized monoclonal antibody against VEGF, whereas ranibizumab is a humanized antigen binding fragment against VEGF, and both proteins were genetically engineered from the same murine monoclonal antibody against VEGF.…”

Section: Introductionmentioning

confidence: 99%

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

Schouten

Heij

Webers

et al. 2008

Graefes Arch Clin Exp Ophthalmol

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Aim To provide evidence for the effect of bevacizumab on visual acuity (VA) and central retinal thickness (CRT) in exudative age-related macular degeneration Methods A systematic review of all articles of bevacizumab for exudative AMD was conducted. Articles published up to March 2008 were identified in Medline, Embase, the Cochrane Controlled Trials Register and references from included articles. Search terms were "Bevacizumab or Avastin" and "Macula* or ARMD or AMD or intra(-) vitreal or intra(-)vitreous". Three observers participated in the data retrieval and assignment of the quality scores. Results A total of 561 articles were retrieved. Three randomised controlled trials (RCT) and 23 before-and-after studies of patients (n=1,435) who had received bevacizumab were published. Inclusion criteria varied. Lack of masking was the main methodological shortcoming. These RCTs showed that bevacizumab is more effective than PDT. Bevacizumab was given intravenously or as intravitreal injection. The latter was given once, or repeatedly every 4 weeks, and with or without additional injection when a recurrence occurred, mostly based on visual acuity and/or findings from optical coherence tomography. After intravenous administration, the weighted mean change in VA was +12.8 ETDRS letters (range +11 to +14) and the weighted mean change for CRT was −129 μm (range −100 to −202). For the 23 studies with intravitreal injections, the change in VA was +8.6 letters (range +2 to +26) and the change in CRT was −90 μm (range −46 to −190). The incidence of adverse events was low. The change in VA was 2.7 letters higher for studies with a higher quality vs lower quality. Conclusion Visual acuity improves and central retinal thickness decreases in patients with exudative AMD after bevacizumab. There is no reasonable doubt that this is caused by bevacizumab. It is likely that a randomised controlled trial will show that bevacizumab is equivalent in effect to ranibizumab, which showed a change in ETDRS of +5.9 letters for occult or minimally classic CNV and +9.8 letters for classic CNV after three monthly injections in two large RCTs.

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Section: Introductionmentioning

confidence: 99%

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

Schouten

Heij

Webers

et al. 2008

Graefes Arch Clin Exp Ophthalmol

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“…This aptamer binds to VEGF 165 with extremely high affinity (K d ϭ 50 pM), and animal studies and clinical data have demonstrated the efficacy of the aptamer in preventing blood vessel growth and arresting the progression of wet AMD (8,(11)(12)(13)(14). However, the detailed molecular mechanism by which this aptamer achieves isoform-specific inhibition of VEGF 165 is not well understood.…”

mentioning

confidence: 99%

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

Lee

Canny²,

Erkenez³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

212

170

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Aptamers recognize their targets with extraordinary affinity and specificity. The aptamer-based therapeutic, Macugen, is derived from a modified 2 fluoro pyrimidine RNA inhibitor to vascular endothelial growth factor (VEGF) and is now being used to treat the wet form of age-related macular degeneration. This VEGF 165 aptamer binds specifically to the VEGF165 isoform, a dimeric protein with a receptor-binding domain and a heparin-binding domain (HBD). To understand the molecular recognition between VEGF and this aptamer, binding experiments were used to show that the HBD contributes the majority of binding energy in the VEGF 165-aptamer complex. A tissue culture-based competition assay demonstrated that the HBD effectively competes with VEGF165 for aptamer binding in vivo. Comparison of NMR spectra revealed that structural features of the smaller HBD-aptamer complex are present in the full-length VEGF 164-aptamer complex. These data show that the HBD provides the binding site for the aptamer and is the primary determinant for the affinity and specificity in the VEGF 165-aptamer complex.age-related macular degeneration ͉ Macugen ͉ RNA ͉ NMR

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“…[26][27][28][29] For the last decade, anti-VEGF reagents have been developed and approved for clinical use against these neovascular ocular diseases. [30][31][32] Now, the role of VEGF in the progress of retinal diseases is widely recognized in the ophthalmological field. [33][34][35] Surprisingly, we found that Vegf gene deletion induced in retinal pigment epithelium (RPE) cells in the adult mature retina in mice rapidly led to degeneration of the choriocapillaris and the cone photoreceptors, whereas Hif-1α and/or Hif-2α knockout mice exhibited no such phenotype 34 (Fig.…”

Section: Hypoxia Response In Retinal Pathophysiologymentioning

confidence: 99%

Roles of Hypoxia Response in Retinal Development and Pathophysiology

Kurihara

2017

Keio j. med

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The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-typespecific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

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Pegaptanib for Neovascular Age-Related Macular Degeneration

Abstract: Pegaptanib for neovascular age-related macular degenerationGragoudas, E.S.; Adamis, A.P.; Cunningham, E.T.; Feinsod, M.; Guyer, D.R.; Study group members AMC, :; Schlingemann, R.O.

Cited by 2,095 publications

References 23 publications

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅

Roles of Hypoxia Response in Retinal Development and Pathophysiology

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Pegaptanib for Neovascular Age-Related Macular Degeneration

Abstract: Pegaptanib for neovascular age-related macular degenerationGragoudas, E.S.; Adamis, A.P.; Cunningham, E.T.; Feinsod, M.; Guyer, D.R.; Study group members AMC, :; Schlingemann, R.O.

Cited by 2,095 publications

References 23 publications

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF 165

Roles of Hypoxia Response in Retinal Development and Pathophysiology

Contact Info

Product

Resources

About

A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF ₁₆₅