RNA Aptamer-directed Anticoagulant Therapy

描述（由申请人提供）：历史上，未分离肝素已用于治疗和预防血栓栓塞性疾病。然而，由于肝素相关的并发症（如出血），低分子量肝素（LMWHs）已被开发出来，并被用于代替未分离肝素。低分子肝素已被证明是有效的抗血栓药物；然而，低分子量肝素的作用不能被轻易逆转，而未分离的肝素可以被硫酸鱼精蛋白逆转。本提案的总体目标是开发一种抗凝血酶（ATIII）特异性RNA适配体，将低分子肝素的安全性和有效性与未分离肝素的可逆性相结合。为了实现这一目标，该适体的寡核苷酸解毒剂将被开发出来，用于快速逆转适体的抗凝血特性。

DESCRIPTION (provided by applicant): Historically, unfractionated heparin has been used in the treatment and prevention of thromboembolic disorders. However, due to complications associated with heparin (such as bleeding), low molecular weight heparins (LMWHs) have been developed and are being used in place of unfractionated heparin. LMWHs have proven effective as antithrombotic agents; however, the effects of LMWHs cannot be readily reversed while unfractionated heparin can be reversed by protamine sulfate. The overall goal of this proposal is to develop an antithrombin (ATIII)-specific RNA aptamer that will combine the safely and efficacy of LMWH with the reversibility of unfractionated heparin. To accomplish this goal, an oligonucleotide antidote for this aptamer that will be used to rapidly reverse the anticoagulant properties of the aptamer will be developed. Proof of this concept is established by the development of an RNA aptamer and RNA aptamer antidote directed against coagulation factor Xa. In collaboration with this group, an antidote-controlled ATIII-specific RNA aptamer will be developed. This aptamer will mimic the action of LMWH by binding to the D-helix of ATIII and enhance ATIII inhibition of factor Xa. This aptamer/antidote pair will have advantages over LMWHs because it will not only be able to control thrombosis similar to LMWHs but the availability of an antidote will allow for better therapeutic regulation and intervention. The experiments proposed in this proposal will characterize this family of antithrombin-specific RNA aptamers using both in vitro and in vivo approaches.