14 Perspectives of Aptamers for Medical Applications
421
function (Platelet Function Analyzer (PFA-100), IC50: 0.5–0.9 mg/mL and Cone
and Plate Analyzer (CPA), IC50: 0.1–0.4 mg/mL in citrated blood) at comparable
concentrations in all groups.
14.3.2.2 Thrombosis
Thrombosis, as seen in ischemic stroke, cardiovascular disease, carotid artery disease,
and peripheral vascular disease, is the leading cause of death and a leading cause
of major disability worldwide [87]. The main therapeutic agent that has been used
to treat occlusive thrombosis is recombinant tissue plasminogen activator (rTPA),
which is approved for both acute coronary thrombosis and is chemic stroke with a
limitations such as that it can only achieve approximately 30% recanalization, and
re-occlusion commonly occurs after primary thrombolysis, resulting in the loss of
initial improvement.
VWF can interact with glycoprotein Ib-alpha (gpIba) on the platelet surface to
induce platelet adhesion to the vessel wall. Inhibition of VWF represents an attractive target in arterial thrombosis, and it may be superior to traditional therapies. A
preclinical study from Duke University used VWF aptamer DTRI-031 [88] to verify
its ability as a potent anti-platelet agent to prevent platelet-rich thrombus formation
in a murine carotid injury model as well as in small and large animal models of
recanalization of platelet-rich occluded vessels. The results of the study suggest that
targeting VWF with an antidote-controllable aptamer potentially represents an effective and safer treatment scheme for thrombosis patients having platelet-rich arterial
occlusions in the brain, heart, or periphery.
Duke clinical research institute finished leading a Phase 2, randomized, partially
blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes
(RADAR trial) [89].
Anticoagulant therapy is a cornerstone of treatment for patients with acute coronary syndromes (ACS) and is vital to the safe conduct of percutaneous coronary interventions (PCI); however, more effective antithrombotic therapies inherently increase
bleeding. Novel approaches that maintain or improve efficacy without increasing
bleeding hazards are needed.
14.3.2.3 Blood Disorder
Acquired thrombotic thrombocytopenic purpura (aTTP) [90] is a blood disorder
that can result in severe organ damage due to enhanced platelet aggregation by
ultra-large VWF multimers. The anti-VWF A1 aptamer ARC1779 (Archemix) was
developed as an antithrombotic agent to be used in patients with aTTP, which showed
sufficient inhibitory effects on VWF activity without any severe bleeding events in a
randomized control trial [91]. ARC1779 was even evaluated in a phase 2 clinical trial
421
function (Platelet Function Analyzer (PFA-100), IC50: 0.5–0.9 mg/mL and Cone
and Plate Analyzer (CPA), IC50: 0.1–0.4 mg/mL in citrated blood) at comparable
concentrations in all groups.
14.3.2.2 Thrombosis
Thrombosis, as seen in ischemic stroke, cardiovascular disease, carotid artery disease,
and peripheral vascular disease, is the leading cause of death and a leading cause
of major disability worldwide [87]. The main therapeutic agent that has been used
to treat occlusive thrombosis is recombinant tissue plasminogen activator (rTPA),
which is approved for both acute coronary thrombosis and is chemic stroke with a
limitations such as that it can only achieve approximately 30% recanalization, and
re-occlusion commonly occurs after primary thrombolysis, resulting in the loss of
initial improvement.
VWF can interact with glycoprotein Ib-alpha (gpIba) on the platelet surface to
induce platelet adhesion to the vessel wall. Inhibition of VWF represents an attractive target in arterial thrombosis, and it may be superior to traditional therapies. A
preclinical study from Duke University used VWF aptamer DTRI-031 [88] to verify
its ability as a potent anti-platelet agent to prevent platelet-rich thrombus formation
in a murine carotid injury model as well as in small and large animal models of
recanalization of platelet-rich occluded vessels. The results of the study suggest that
targeting VWF with an antidote-controllable aptamer potentially represents an effective and safer treatment scheme for thrombosis patients having platelet-rich arterial
occlusions in the brain, heart, or periphery.
Duke clinical research institute finished leading a Phase 2, randomized, partially
blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes
(RADAR trial) [89].
Anticoagulant therapy is a cornerstone of treatment for patients with acute coronary syndromes (ACS) and is vital to the safe conduct of percutaneous coronary interventions (PCI); however, more effective antithrombotic therapies inherently increase
bleeding. Novel approaches that maintain or improve efficacy without increasing
bleeding hazards are needed.
14.3.2.3 Blood Disorder
Acquired thrombotic thrombocytopenic purpura (aTTP) [90] is a blood disorder
that can result in severe organ damage due to enhanced platelet aggregation by
ultra-large VWF multimers. The anti-VWF A1 aptamer ARC1779 (Archemix) was
developed as an antithrombotic agent to be used in patients with aTTP, which showed
sufficient inhibitory effects on VWF activity without any severe bleeding events in a
randomized control trial [91]. ARC1779 was even evaluated in a phase 2 clinical trial