Antidote-mediated control of an anticoagulant aptamer in vivo.
Patient 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.
Rusconi
Christopher P
CP
Department of Surgery, Center for Translational Research, Duke University Medical Center, Campus Box 2601, Durham, North Carolina 27710, USA.
Roberts
Joseph D
JD
Pitoc
George A
GA
Nimjee
Shahid M
SM
White
Rebekah R
RR
Quick
George
G
Scardino
Elizabeth
E
Fay
William P
WP
Sullenger
Bruce A
BA
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects*; D000931:Antidotes / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D002341:Carotid Artery Thrombosis / Q000188:drug therapy; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006470:Hemorrhage / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects*; D013552:Swine; D016896:Treatment Outcome
D000925:Anticoagulants; D000931:Antidotes; D009841:Oligonucleotides