Development of universal antidotes to control aptamer activity

• Published in: Nature medicine Vol. 15; no. 10; pp. 1224 - 1228
• Main Authors: Bompiani, Kristin M, Heidel, Jeremy D, Liu, Joanna Yi-Ching, Mack, Brendan C, Davis, Mark E, Leong, Kam W, Oney, Sabah, Sullenger, Bruce A, Lam, Ruby T S, Blake, Charlene M, Quick, George
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2009; Nature Publishing Group
• Subjects: Adverse and side effects; Anticoagulants - adverse effects; Anticoagulants - pharmacology; Antidotes; Antidotes - administration & dosage; Antidotes - pharmacology; Aptamers, Nucleotide - classification; Aptamers, Nucleotide - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug Delivery Systems; Drug Design; Drug therapy; Drugs; Factor IX - antagonists & inhibitors; Factor Xa Inhibitors; Health aspects; Humans; Infectious Diseases; Metabolic Diseases; Molecular biology; Molecular Medicine; Neurosciences; Nucleic Acid Conformation - drug effects; Oligonucleotides - pharmacology; Pharmacology; Polymers; Protamines - pharmacology; Side effects; technical-report; Time Factors; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1990

In an effort to develop safer therapeutic agents and to limit unintended side effects, Sabah Oney and her colleagues have designed a set of antidote molecules for a series of aptamers exhibiting anticoagulant activities. These so-called universal antidotes are shown to sequester circulating aptamers and reverse their activity, irrespective of the primary sequence and folded structure of the aptamer. With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo . The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.