Development of Novel Antidote Controlled Antithrombotic Aptamers
Abstract
Thrombosis is initiated by platelets and leads to cardio-, cerebro-, and peripheral
vascular disease, the leading causes of morbidity and mortality in the western world.
Antiplatelet drugs have improved clinical outcomes for thrombosis patients. However,
their expanded use is limited by hemorrhage at high concentrations and sub-therapeutic
activity at lower doses. Thus, development of new antiplatelet agents with improved
safety and efficacy is a medical priority.
VWF is a multimeric plasma glycoprotein that plays a critical role in platelet-mediated
thrombus formation and presents an attractive target for antiplatelet therapy. To
this end, I have isolated and characterized aptamer molecules that bind to VWF with
high affinity and have shown that some of these aptamer molecules could inhibit platelet
activation/aggregation in vitro and in vivo. Furthermore, I designed antidote molecules
that can reverse the effects of the aptamer molecules, restoring platelet function
quickly and effectively. This project has yielded the first antidote controlled antiplatelet
agent and may lead to significant improvements in thrombosis therapy.
Thrombin is a plasma protein that plays a critical role in thrombosis. Currently,
available antithrombin agents are efficacious in preventing coagulation but do not
significantly affect platelet activation and aggregation, both essential components
of thrombus formation. Therefore, I tested two aptamer molecules that bind to mutually
exclusive exosites on thrombin and, when used together, synergistically inhibit both
coagulation and platelet activation. I demonstrated that this method could potentially
lead to the development of effective antithrombotic therapies.
With an ever-increasing number of people taking multiple 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. Therefore, I described the development of a set of antidote
molecules that are capable of counteracting the effects of an entire class of therapeutic
agents, i.e. aptamers, including those that I generated against VWF. I demonstrated
that protein and polymer-based molecules that capture oligonucleotides can reverse
the activity of aptamers in vitro and in vivo.
Type
DissertationDepartment
Genetics and GenomicsSubject
Biology, GeneticsHealth Sciences, Pharmacology
Biology, Genetics
Aptamers
Antidote
Thrombosis
VWF
Platelets
Antiplatelet
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https://hdl.handle.net/10161/608Citation
Oney, Sabah (2008). Development of Novel Antidote Controlled Antithrombotic Aptamers. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/608.Collections
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