Translating Nucleic Acid Aptamers to Antithrombotic Drugs in Cardiovascular Medicine

Povsic, Thomas J.; Sullenger, Bruce A.; Zelenkofske, Steven L.; Rusconi, Christopher P.; Becker, Richard C.

doi:10.1007/s12265-010-9230-6

Cited by 13 publications

(14 citation statements)

References 63 publications

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“…From a therapeutic standpoint, aptamers have been generated against a variety of human proteins for the treatment of both benign and malignant conditions. They have been used to prevent adhesion and aggregation of platelets for anticoagulation [16], diseased cells in sickle cell disease [17], and targeting of amyloid in Alzheimer’s [18] to name a few. Significant progress has been made in targeting factor IXa for specific and easily reversible anticoagulation using the aptamer/antidote pair REG1 [19].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells

Talbot

Bhattacharya

et al. 2011

Surgery

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Introduction We report pharmacokinetic (PK) data, evaluation of modifications for increased stability, evaluation for cellular uptake, and mediation of regression of breast cancer for the aptamer OPN-R3. Methods OPN-R3 aptamer was assessed for PK data in vivo with additional comparison of IV and SQ dosing. Five aptamer variants were generated by differential 2’-O-methylation for comparison with parent. OPN-R3-Cy3 was incubated with MDA-MB231 cells and cellular uptake evaluated under confocal microscopy. Mice were treated with OPN-R3, mutant, or saline three weeks after inoculation with MDA-MB231 cells and tumor size was evaluated. Results OPN-R3 PK data were: t1/2 7.76 hrs, Tmax 3 hrs, Cmax 13.2 mmol/L, MRT 9 hrs, AUC (0-t) 161.9 mmol-hr/L, Kd 57.2 nM. Half-life was higher when given IV versus SQ (E1/2 7.93 hrs vs 0.74 hrs). 2’ methylation of all available bases increased unmodified aptamer stability and affinity (t1/2 6.2 hrs, Kd 520 nM) but this did not improve on parent aptamer (t1/2 7.78 hours, Kd 18 nM). The aptamer remained extracellular. OPN-R3 caused regression of tumor to levels seen at 1 wk after tumor inoculation. Conclusions We show efficacy of OPN-R3 for reversing growth of breast cancer cells with adequate pharmacokinetic stability for clinical application.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells

Talbot

Bhattacharya

et al. 2011

Surgery

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“…Additionally, several aptamers targeting VWF have been developed 64, 65 , and the aptamer ARC1779 advanced in clinical trials for acute coronary syndromes, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura, among other indications (Table 2) 66–68 . The development, mechanisms, and clinical trials of the VWF aptamer have been reviewed extensively elsewhere 6, 29, 69, 70 , and we refer the reader to the cited literature for additional discussion on these aptamers.…”

Section: Other Aptamers Targeting Coagulation Proteinsmentioning

confidence: 99%

Modulation of the Coagulation Cascade Using Aptamers

Woodruff

Sullenger

2015

ATVB

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As a novel class of therapeutics, aptamers, or nucleic acid ligands, have garnered clinical interest due to the ease of isolating a highly specific aptamer against a wide range of targets, their chemical flexibility and synthesis, as well as their inherent ability to have their inhibitory ability reversed. The following review details the development and molecular mechanisms of aptamers targeting specific proteases in the coagulation cascade. The ability of these anticoagulant aptamers to bind to and inhibit exosite function rather than binding within the active site highlights the importance of exosites in blocking protein function. As both exosite inhibitors and reversible agents, the use of aptamers is a promising strategy for future therapeutics.

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“…The development of the 9.3t aptamer and others have been accompanied by the development of antidotes for rapid reversal of aptamer anticoagulatory effects in the form of complementary oligonucleotides (57,60) or nucleic acid binding polymers (61). A modified version of 9.3t (RB006) and a complementary oligonucleotide antidote (RB007), collectively named the REG1 Anticoagulation System, is currently in clinical trials phase 2B (for a review on this system see (6,36)). …”

Section: General Properties Of Serine Proteases -mentioning

confidence: 99%

Nucleic Acid Aptamers Against Proteases

Dupont

Andersen²,

Bøtkjær³

et al. 2011

CMC

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Proteases are potential or realized therapeutic targets in a wide variety of pathological conditions. Moreover, proteases are classical subjects for studies of enzymatic and regulatory mechanisms. We here review the literature on nucleic acid aptamers selected with proteases as targets. Designing small molecule protease inhibitors of sufficient specificity has proved a daunting task. Aptamers seem to represent a promising alternative. In our review, we concentrate on biochemical mechanisms of aptamer selection, proteinaptamer recognition, protease inhibition, and advantages of aptamers for pharmacological intervention with pathophysiological functions of proteases. Aptamers can be selected so that they bind their targets highly specifically and with affinities corresponding to K D values in the nM range. Aptamers can be selected so that they recognize their targets conformation-specifically, for instance with vastly different affinities to zymogen and active enzyme forms. Aptamers can be selected so that they inhibit the enzyme activity of the target proteases, but also so that they inhibit functionally important exosite interactions, for instance cofactor binding. Several protease inhibiting aptamers, mostly directed against blood coagulation, are in clinical trials as antithrombotic drugs. Several of the studies on protease-binding aptamers have been pioneering and trend-setting in the field. The work with protease-binding aptamers also demonstrates many interesting examples of non-standard selection strategies and of new principles for regulating the activity of the inhibitory action of aptamers of general interest to researchers working with nucleic acid aptamers.

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Translating Nucleic Acid Aptamers to Antithrombotic Drugs in Cardiovascular Medicine

Cited by 13 publications

References 63 publications

Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells

Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells

Modulation of the Coagulation Cascade Using Aptamers

Nucleic Acid Aptamers Against Proteases

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