Gene therapy progress and prospects: RNA aptamers

Que-Gewirth, N S; Sullenger, Bruce A.

doi:10.1038/sj.gt.3302900

Cited by 210 publications

(131 citation statements)

References 60 publications

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“…Therefore, aptamer-based therapy is a potent therapeutic strategy that may replace many antibody therapies in the future. Recently, the U.S. Food and Drug Aministration approved antivascular endothelial growth factor aptamer as the treatment for age-related macular degeneration (40). Our study also provides strong evidence for the clinical efficacy of RNA aptamers.…”

Section: Discussionsupporting

confidence: 60%

Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

Wang

Takeuchi

Sonobe

et al. 2008

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

110

150

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Section: Discussionsupporting

confidence: 60%

Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

Wang

Takeuchi

Sonobe

et al. 2008

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

110

150

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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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“…RNA aptamers are nanomolecules that can recognize their targets with extremely high affinity. This class of compounds provides unique advantages as therapeutic agents, such as amenability to chemical modifications, ease of production, and low immunogenicity (11,12).…”

Section: Myeloid-derived Suppressor Cells (Mdsc Cd11bmentioning

confidence: 99%

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

et al. 2012

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In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloidderived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-a (IL4Ra or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Ra aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumorinfiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Ra signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Ra signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Res; 72(6); 1373-83. Ó2012 AACR.

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Gene therapy progress and prospects: RNA aptamers

Cited by 210 publications

References 60 publications

Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

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

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

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