A neutralizable aptamer for safer anti-thrombotic therapy
Venous thrombosis is a serious, potentially fatal condition that affects approximately 1 in 1000 adults, with an economic burden culminating in over $5 billion in costs. While effective, current antithrombotic drugs, which are among the most widely administered therapies, often induce adverse complications such as hemorrhaging. There are several factors that influence the development of adverse events (e.g. number of antithrombotic agents used, underlying condition, severity of surgical intervention); however, age is a major contributing factor. Studies have shown that there is a 46% increase in risk of major bleeding for every 10 years above the age of 40. Thus, there is a clear and urgent need for antithrombotics that can effectively eliminate blood clots whilst not promoting excessive bleeding.
Dr. Bruce Sullenger and colleagues at Duke University have developed a novel RNA-based aptamer targeting the major coagulative molecule Von Willebrand factor (vWF), which induces striking anti-coagulative properties in several in vivo thrombosis models. This effect was greater than that which was produced by the commonly used modality tissue plasminogen activator (rTPA, Fig. 1). More importantly, Dr. Sullenger et al. have developed a corresponding antidote that is able to potently neutralize the anti-coagulative effects of the vWF-targeting aptamer, greatly mitigating the potential of serious adverse events, including hemorrhage.
This invention has encouraging implications for the treatment of ongoing thrombotic events; however, given the added level of safety of this methodology (i.e. antidote-mediated neutralization), this therapy may potentially also be used for the prevention of blood clots.
In addition to the ability to neutralize the therapeutic aptamer with an antidote, this aptamer is smaller, less susceptible to nuclease degradation, and exhibits increased circulation times compared to predecessor vWF aptamers.
Duke File (IDF) Number
- Sullenger, Bruce
- Layzer, Juliana
- Nimjee, Shahid
- Pitoc, George
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- Gopalakrishnan, Karthik