What clinical use aptamers may have?
['In murine tumor models, the aptamer-targeted siRNA-mediated NMD inhibition in tumor cells led to significant inhibition of tumor growth, which was superior to best-in-class "conventional" cancer vaccination protocols. Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumors leading to their immune recognition and rejection.', 'This study is focused on one aptamer (termed A2). Transfection of this molecule into HPV16-transformed cells resulted in inhibition of cell proliferation (shown using real-time cell electronic sensing and MTT assays) due to the induction of apoptosis (as demonstrated by Annexin V/propidium iodide staining).', 'Transfection of cells with A2 was correlated with the loss of E7 and the induction of apoptosis.', 'Aptamers specific for a number of cellular and viral proteins have been documented previously; one aptamer (Macugen) is approved for clinical use and several others are in clinical trials.', 'The high binding affinity and specificity of aptamers allows for isolation of an artificial ligand for theoretically any therapeutic target of interest.', 'Aptamers are a special class of nucleic acid molecules that are beginning to be investigated for clinical use. These small RNA/DNA molecules can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets; they are essentially a chemical equivalent of antibodies. Aptamers have the advantage of being highly specific, relatively small in size, and non-immunogenic.', 'In the last two decades, many aptamers have been clinically developed as inhibitors for targets such as vascular endothelial growth factor (VEGF) and thrombin.', 'The first aptamer based therapeutic was FDA approved in 2004 for the treatment of age-related macular degeneration and several other aptamers are currently being evaluated in clinical trials.', 'Preclinical studies using aptamer-siRNA chimeras and aptamer targeted nanoparticle therapeutics have been very successful in mouse models of cancer and HIV.', 'In summary aptamers are in several stages of development, from pre-clinical studies to clinical trials and even as FDA approved therapeutics.', 'In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation.', 'An assortment of non-viral carriers including liposomes, peptides, polymers, and aptamers are being evaluated for their ability to shepherd siRNA to the target tissue and cross the plasma membrane barrier into the cell.', 'In addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered protease-activated receptor antagonist that targets thrombin-induced platelet aggregation, and anti-von Willebrand factor aptamers show tremendous promise in refining antiplatelet therapy by targeting different receptors and molecules.', 'First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers', 'ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes.', 'This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.', 'Wet age-related macular degeneration and diabetic retinopathy are pathological consequences of vascular endothelial growth factor (VEGF) release as a reaction to deficiency of oxygen and nutrients in the macular cells.', 'FDA recently approved two drugs specifically aimed at VEGF, bevacizumab, a humanized monoclonal antibody, and pegaptinib, a pegylated aptamer with application in ophthalmic pathologies.', 'Delivery of double-stranded DNA thioaptamers into HIV-1 infected cells for antiviral activity', 'Our lead thioaptamer, R12-2, targets the RNase H domain of the HIV-1 reverse transcriptase (RT) and inhibits viral infection in U373-MAGI-CCR5 cells.', 'In this report, we demonstrate that monothioate-modified DNA duplex oligonucleotides can be efficiently delivered into cells by liposome-based transfection agents to inhibit HIV replication.', 'Nucleic acid aptamers in therapeutic anticoagulation', 'Pegaptanib sodium for the treatment of neovascular age-related macular degeneration', 'Pegaptanib sodium is one of the first therapeutics belonging to the class of compounds known as aptamers.', 'The article highlights and summarises the results of the multi-centre, randomised, sham-controlled clinical trials with pegaptanib sodium to treat subfoveal choroidal neovascularisation in AMD. In addition, the safety profile is reviewed.', 'Regulatable aptamers in medicine: focus on antithrombotic strategies', 'After a decade of intensive research, technology development and initial clinical evaluation, aptamers have now demonstrated broad potential as direct protein ligands and inhibitors, and thus represent an exciting class of compounds for the development of new therapeutic and diagnostic agents. ', 'Two R-aptamers (R10-60 and D-R15-8) with the predominant shared characteristics were selected for further study on primary human chronic lymphocytic leukemia (CLL) B cells, which are well known to be difficult to transfect and activate.', 'Together, these findings suggest that the sequence compositions in R-aptamers that promote multimerization and contain optimal ISS CpG motifs facilitate the delivery of ISS-ODN to CLL cells and enhance the activation of these cells.', 'In particular, the use of aptamers for the alleviation of blood clotting and the treatment of AIDS are considered.', 'We synthesized an RNA aptamer probe specific for human CD4 using a reported sequence and investigated the potential use of this probe in cell phenotyping. Studies in cultured cells demonstrated that the synthetic CD4 aptamer had a nearly identical cell-binding specificity as the standard CD4 antibody. Fluorescent microscopy confirmed that the aptamer and antibody generated the same CD4 staining pattern in cells without competing with one another.', 'transfection of HPV16-transformed cells with A2 appeared to result in the loss of E7 and rise in pRb levels']
['In the clinic, aptamers may be used to enhance the antigenicity of disseminated tumors, leading to their immune recognition and rejection; to target HPV16 E7 oncoprotein, inhibiting cell proliferation and activating apoptosis of infected cells; to act as inhibitors for targets such as VEGF, in age-related macular degeneration, and thrombin, or von Willebrand factor, in patients with acute coronary syndromes; to target the RNase H domain of the HIV-1 reverse transcriptase and inhibit viral replication; to transfect and activate B cells in human chronic lymphocytic leukemia (CLL); or finally, to be used as probes in CD4-cell phenotyping.']
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