10 Aptamers for Thrombotic Diseases
309
In addition, ARC5692 maintained valve competency equal to enoxaparin and better
than ARC15105. The results also revealed that ARC15105 significantly decreased
platelet aggregation, and only ARC5692 prevented vein wall fibrosis.No adverse
bleeding events were observed. The anti-P-selectin aptamer not only improved iliac
vein recanalization but also preserved valve competency and decreased vein wall
fibrosis. Therefore, anti-P-selectin aptamer may be an ideal strategy for the treatment
and prophylaxis of DVT that warrants clinical trials [132].
In short, compared to the traditional antiplatelet agents, vWF antagonists can
reduce bleeding risk because they selectively inhibit platelet activation under high
shear stress in pathological environments. Thus anti-vWF aptamers are potential
substitutes of GP IIb/IIIa antagonists, especially in the setting of vWF-mediated
thromboses such as CAD, ACS, AMI, PCI procedures, and peripheral vascular
diseases. Aside from antithrombotic studies, a phase 2 study of ARC1779 in
patients with von Willebrand factor-related platelet function disorders (von Willebrand Disease Type-2b) and purpura thrombotic thrombocytopenic (TTP) has been
completed (NCT00632242) (https://clinicaltrials.gov).
10.9.2 Aptamers Against PDGFRβ
Romanelli et al. reported a more selective delivery strategy of the mimetic peptide
(MP) to cardiomyocytes. They designed a novel aptamer-peptide chimera by conjugation of MP directly to aptamer Gint4.T (a 3
-propargyl adenosine at the 3
end in place of standard adenosine) targeting the platelet-derived growth factor
receptor-β (PDGFRβ), a receptor expressed in cardiomyocytes. Western blot analysis
showed that Gint4.T-MP targeted the cardiac cells (HL-1) and restored the L-type
calcium channel (LTCC) protein Cavα1.2 levels. Gint4.T-MP also recovered LTCCdependent calcium fluxes in cardiac cells in a fluorometric cell-based assay. The
experiments demonstrated that the Gint4.T-MP chimera was internalized in cardiac
cells and then the functional targeting of MP to LTCC. Results suggested that the
aptamer-peptide chimera is a safe and selective delivery strategy for the treatment
of cardiac disorders associated with LTCC abnormalities. The novel chimera can
recover myocardial contractility in cardiac cells in pathological heart conditions.
Since PDGFRβ in addition to cardiomyocytes is also expressed in other cell types, the
authors suggested broader applicability of aptamer-peptide chimera for the selective
delivery and intracellular penetration of small therapeutic peptides in several other
diseases, for example, cancers [133].
10.9.3 Conclusion and Perspectives
In conclusion, antithrombotic aptamers were developed as therapeutic agents for
several highly attractive characteristics combined with both antibodies and small
309
In addition, ARC5692 maintained valve competency equal to enoxaparin and better
than ARC15105. The results also revealed that ARC15105 significantly decreased
platelet aggregation, and only ARC5692 prevented vein wall fibrosis.No adverse
bleeding events were observed. The anti-P-selectin aptamer not only improved iliac
vein recanalization but also preserved valve competency and decreased vein wall
fibrosis. Therefore, anti-P-selectin aptamer may be an ideal strategy for the treatment
and prophylaxis of DVT that warrants clinical trials [132].
In short, compared to the traditional antiplatelet agents, vWF antagonists can
reduce bleeding risk because they selectively inhibit platelet activation under high
shear stress in pathological environments. Thus anti-vWF aptamers are potential
substitutes of GP IIb/IIIa antagonists, especially in the setting of vWF-mediated
thromboses such as CAD, ACS, AMI, PCI procedures, and peripheral vascular
diseases. Aside from antithrombotic studies, a phase 2 study of ARC1779 in
patients with von Willebrand factor-related platelet function disorders (von Willebrand Disease Type-2b) and purpura thrombotic thrombocytopenic (TTP) has been
completed (NCT00632242) (https://clinicaltrials.gov).
10.9.2 Aptamers Against PDGFRβ
Romanelli et al. reported a more selective delivery strategy of the mimetic peptide
(MP) to cardiomyocytes. They designed a novel aptamer-peptide chimera by conjugation of MP directly to aptamer Gint4.T (a 3
-propargyl adenosine at the 3
end in place of standard adenosine) targeting the platelet-derived growth factor
receptor-β (PDGFRβ), a receptor expressed in cardiomyocytes. Western blot analysis
showed that Gint4.T-MP targeted the cardiac cells (HL-1) and restored the L-type
calcium channel (LTCC) protein Cavα1.2 levels. Gint4.T-MP also recovered LTCCdependent calcium fluxes in cardiac cells in a fluorometric cell-based assay. The
experiments demonstrated that the Gint4.T-MP chimera was internalized in cardiac
cells and then the functional targeting of MP to LTCC. Results suggested that the
aptamer-peptide chimera is a safe and selective delivery strategy for the treatment
of cardiac disorders associated with LTCC abnormalities. The novel chimera can
recover myocardial contractility in cardiac cells in pathological heart conditions.
Since PDGFRβ in addition to cardiomyocytes is also expressed in other cell types, the
authors suggested broader applicability of aptamer-peptide chimera for the selective
delivery and intracellular penetration of small therapeutic peptides in several other
diseases, for example, cancers [133].
10.9.3 Conclusion and Perspectives
In conclusion, antithrombotic aptamers were developed as therapeutic agents for
several highly attractive characteristics combined with both antibodies and small