A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF
            <sub>165</sub>

Lee, Joon‐Hwa; Canny, Marella D.; Erkenez, A. De; Krilleke, Dominik; Ng, Y. Jack; Shima, David T.; Pardi, Arthur; Jucker, Fiona M.

doi:10.1073/pnas.0509069102

Cited by 212 publications

(179 citation statements)

References 35 publications

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“…4,15 Remarkably, the number of aptamers that show inhibitory action against therapeutically relevant targets is rapidly increasing. [16][17][18] However, aptamers raised against a purified membrane protein often lose their recognition capacity in the cellular context. 19,20 Cell-SELEX has recently taken the aptamer field one step further by creating ligands against complex membrane molecular targets in their native environment.…”

Section: Discussionmentioning

confidence: 99%

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Zueva

Rubio

Ducongé

et al. 2010

Intl Journal of Cancer

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Metastasis, the capacity of tumour cells to disseminate and grow at distant sites, is the main factor in cancer mortality. Compounds inhibiting migration and invasion of cancer cells are promising candidates for anticancer therapy strategies. We have generated nuclease-resistant RNA ligands (aptamers) recognizing highly metastatic cells with high affinity and specificity, and inhibiting their migratory and invasive potentials. Aptamers were generated by a cell-based subtractive SELEX technology using isogenic cell lines with similar tumorigenic potentials but opposite metastatic aggressiveness. Two aptamers, E37 and E10, bound specifically to the metastatically aggressive cell line and altered the phosphorylation of several tyrosine kinases. Fluorescent microscopy showed intracellular uptake of E37, in contrast to membrane binding of E10. Both aptamers inhibited migration of tumour cells in culture (50 and 85% inhibition with respect to control pool for E10 and E37, respectively) while only E10 inhibited cell invasion (275% with respect to control pool). This proof-of-concept study demonstrates the potential of cell-based SELEX to yield ligands that selectively recognize aggressive metastatic cells and inhibit phenotypes linked to metastatic potential.In cancer, a fatal issue is most often the consequence of metastatic spreading, but very few if any chemotherapies address the metastatic process itself. One reason may be that the process by which tumour cells metastasize is a still imperfectly understood succession of different molecular mechanisms. Another reason is that many of these molecular mechanisms pertain both to metastasis and to ubiquitous cellular activities. For instance, cell migration is an important and obligatory factor for the dissemination of tumour cells, as well as a general feature of many normal cells. Hence, it is far from trivial to target selectively the migration of cancer cells and not that of normal cells. Here, we explored new approaches to selectively target and inhibit specifically abnormal, context-irrelevant, cell migration with the aim to produce molecular binders for the recognition and, possibly, the control of metastatic activity.Among iterative selection methods based on Darwin's survival of the fittest, the SELEX (Systematic Evolution of Ligands by EXponential Enrichment) allows the in vitro evolution of small nucleic acid molecules (aptamers) recognizing a specific molecular target.1,2 Aptamers bind cognate targets with high affinity and specificity, assuming stable three-dimensional structures 3 and often perturb their function. 4 Recently, SELEX has been adapted to the recognition of undefined targets in complex environments, in particular in live cells.5 A high level of molecular discrimination can be obtained using subtractive SELEX protocols, where cells from homologous origin, one expressing the target or phenotype of interest and the other not expressing, are used to alternate negative and positive selection steps. Cellbased SELEX has shown its capacity to track ten...

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Section: Discussionmentioning

confidence: 99%

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Zueva

Rubio

Ducongé

et al. 2010

Intl Journal of Cancer

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“…It is an aptamer that binds preferentially to the heparin binding domain of the VEGF protein (Lee et al, 2005), and is marketed to selectively inhibit the "pathologic" VEGF 165 isoform (Usui et al, 2004). It was reported to have a significant but modest clinical effect, with loss of three lines of visual acuity or less (defined as a successful outcome) achieved in 70% of treated, but also in 55% of uninjected controls (Gragoudas et al, 2004).…”

Section: Agents Thatmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…The pegylated, nuclease-stabilized aptamer acts as a selective antagonist of vascular endothelial growth factor (VEGF 165 ) by binding at the heparinbinding domain. 9 VEGF plays a crucial role in angiogenesis and thus in cancer as well as in AMD, where its levels are elevated. Macugen has been shown to retard vision loss and is presently in clinical trials for diabetic macular edema and retinal vein occlusion.…”

Section: Prospectsmentioning

confidence: 99%

Gene therapy progress and prospects: RNA aptamers

2007

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Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody-and small-moleculebased therapeutics owing to their stability, low toxicity, low immunogenicity and improved safety. With the recent approval of the first aptamer drug Macugen by the US FDA, there is great impetus to develop therapeutic aptamers that can target a wide array of disease states. The recent demonstration that aptamer activity can be reversed by the administration of a simple antidote greatly enhances the potential value of aptamers as therapeutic agents.

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

Cited by 212 publications

References 35 publications

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Vascular endothelial growth factor in eye disease

Gene therapy progress and prospects: RNA aptamers

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

Cited by 212 publications

References 35 publications

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Metastasis‐focused cell‐based SELEX generates aptamers inhibiting cell migration and invasion

Vascular endothelial growth factor in eye disease

Gene therapy progress and prospects: RNA aptamers

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Product

Resources

About

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