Nature Biotechnology
22, 1423 - 1428 (2004)
Published online: 17 October 2004; | doi:10.1038/nbt1023
Antidote-mediated control of an anticoagulant aptamer in vivoChristopher P Rusconi1, 3, Joseph D Roberts2, George A Pitoc1, Shahid M Nimjee1, Rebekah R White1, George Quick Jr1, Elizabeth Scardino1, William P Fay2
& Bruce A Sullenger11
Department of Surgery, Center for Translational Research, Duke University Medical Center, Campus Box 2601, Durham, North Carolina 27710, USA. 2
Department of Internal Medicine, University of Michigan Medical Center, 7301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, USA. 3
Present address: Regado Biosciences, Inc., PO Box 14688, Research Triangle Park, North Carolina 27709, USA.
Correspondence should be addressed to Christopher P Rusconi crusconi@regadobiosciences.com or Bruce A Sullenger b.sullenger@cgct.duke.eduPatient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.
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