6 Aptamers for Targeted Therapy
133
pathogenesis-related factors; therefore inhibiting C5 activation may prevent inflammatory tissue damage caused by AMD. Several major components of the complement system proteins play important roles in retinobiology and AMD pathogenesis,
including the complement factor H (CFH), the cleavage products of C3 and C5, and
MAC [6, 27, 28]. A series of studies have proved that inhibiting the activation of
C5 is effective in preventing inflammatory tissue damage caused by AMD [15, 28],
which may be an effective strategy for the treatment of wet and dry AMD [29, 30].
Chi et al. [30] screened an aptamer motif C5C6 (38 nt) of C5 from the 2
-
fluorouracil (2
-F) modified RNA library with nuclease resistance. Furthermore,
a partial RNA library was designed based on motif C5C6, and the aptamer with
C5 inhibitory activity was obtained through eight rounds of partial SELEX, and
its affinity was increased by 10 times compared with that of C5C6. The C5
aptamer ARC1905 was named Zimura, which was modified with 2
-fluorouracil, 2
-
methoxypurine, 3
-idT-cap and 40 kDa-PEG. Zimura and Lucentis were combined
to treat exudative AMD in juvenile patients in a non-randomized, open-label phase
2a clinical trials. The results showed that the mean BCVA increased by more than
three lines in the low, medium, and high dose groups [31, 32]. In addition, a significant percentage of visual acuity improvement was also observed when Zimura was
delivered in combination with Bevacizumab, Ranibizumab, or Aflibercept, which
was superior to the historical control group of Lucentis monotherapy patients. Based
on the apparently positive results, Ophthotech is undergoing phase 2/3 clinical trials
in which Zimura will be applied to treat severe dry AMD [25].
6.3 Aptamers for Targeted Therapy of Coagulation
Disruption of the balance between coagulation and anticoagulation systems leads
to bleeding or thrombosis. In vivo coagulation is a spatially heterogeneous process.
During vascular injury, platelets act as the main hemostatic agents to form blockages
at the injury site. Meanwhile, coagulation factors and related proteins cascade to
form fibrin polymers for secondary hemostasis [33]. Coagulation cascades include
endogenous and exogenous coagulation pathways. In the endogenous coagulation
pathway, FVa-FXa complex formed by FXa is activated by FXII, and FVa is capable
of prothrombin activation and fibrinogen degradation. Furthermore, XIIIa mediates
fibrin cross-linking to form stable fibrin polymers. In the exogenous coagulation
pathway, tissue factor (TF) binds with plasma factor VIIa (FVIIa) to form TF-FVIIa,
promoting the activation of FIX and FX [34]. Natural anticoagulants in vivo can
inhibit the activity of thrombin, including heparin and antithrombin III [35, 36]. In
addition, the thrombo-regulatory protein/protein C pathway and the protein S/tissue
factor pathway inhibitor (TFPI) system have been proved to be effective natural anticoagulants [37]. In 1992, the first aptamer drug for antithrombin was reported [38].
133
pathogenesis-related factors; therefore inhibiting C5 activation may prevent inflammatory tissue damage caused by AMD. Several major components of the complement system proteins play important roles in retinobiology and AMD pathogenesis,
including the complement factor H (CFH), the cleavage products of C3 and C5, and
MAC [6, 27, 28]. A series of studies have proved that inhibiting the activation of
C5 is effective in preventing inflammatory tissue damage caused by AMD [15, 28],
which may be an effective strategy for the treatment of wet and dry AMD [29, 30].
Chi et al. [30] screened an aptamer motif C5C6 (38 nt) of C5 from the 2
-
fluorouracil (2
-F) modified RNA library with nuclease resistance. Furthermore,
a partial RNA library was designed based on motif C5C6, and the aptamer with
C5 inhibitory activity was obtained through eight rounds of partial SELEX, and
its affinity was increased by 10 times compared with that of C5C6. The C5
aptamer ARC1905 was named Zimura, which was modified with 2
-fluorouracil, 2
-
methoxypurine, 3
-idT-cap and 40 kDa-PEG. Zimura and Lucentis were combined
to treat exudative AMD in juvenile patients in a non-randomized, open-label phase
2a clinical trials. The results showed that the mean BCVA increased by more than
three lines in the low, medium, and high dose groups [31, 32]. In addition, a significant percentage of visual acuity improvement was also observed when Zimura was
delivered in combination with Bevacizumab, Ranibizumab, or Aflibercept, which
was superior to the historical control group of Lucentis monotherapy patients. Based
on the apparently positive results, Ophthotech is undergoing phase 2/3 clinical trials
in which Zimura will be applied to treat severe dry AMD [25].
6.3 Aptamers for Targeted Therapy of Coagulation
Disruption of the balance between coagulation and anticoagulation systems leads
to bleeding or thrombosis. In vivo coagulation is a spatially heterogeneous process.
During vascular injury, platelets act as the main hemostatic agents to form blockages
at the injury site. Meanwhile, coagulation factors and related proteins cascade to
form fibrin polymers for secondary hemostasis [33]. Coagulation cascades include
endogenous and exogenous coagulation pathways. In the endogenous coagulation
pathway, FVa-FXa complex formed by FXa is activated by FXII, and FVa is capable
of prothrombin activation and fibrinogen degradation. Furthermore, XIIIa mediates
fibrin cross-linking to form stable fibrin polymers. In the exogenous coagulation
pathway, tissue factor (TF) binds with plasma factor VIIa (FVIIa) to form TF-FVIIa,
promoting the activation of FIX and FX [34]. Natural anticoagulants in vivo can
inhibit the activity of thrombin, including heparin and antithrombin III [35, 36]. In
addition, the thrombo-regulatory protein/protein C pathway and the protein S/tissue
factor pathway inhibitor (TFPI) system have been proved to be effective natural anticoagulants [37]. In 1992, the first aptamer drug for antithrombin was reported [38].