6 Aptamers for Targeted Therapy
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clinical development of mouse encephalitis was inhibited. Gene expression analysis
suggested that the expression of inflammatory genes including IL-23, IL-17, IL-6,
and INFgamma decreased. Lenn et al. [145] screened and optimized the 62 nt RNA
aptamer inhibitors of IL-23 and applied them in the local treatment of psoriasis.
The aptamer penetrated through the complete human skin barrier and entered the
epidermis and dermis to reach a therapeutic level, which can still target endogenous
IL-23 by maintaining its activity and biological conformation after skin penetration.
6.4.2 Aptamers Targeting Tumor Necrosis Factor (TNF)
6.4.2.1 TNF-α
TNF-α is a major pro-inflammatory cytokine and plays an important role in apoptosis,
cell proliferation, and immune response. TNF-α exerts pro-inflammatory or antiinflammatory effects by binding to type I (TNF-RI; p55) or type II (TNF-RII; p75)
receptors and activating different intracellular signal transduction pathways [146].
Orava et al. [147] screened a 25 nt TNF-α DNA aptamer VR11 with G-quadruplex
structure. VR11 specifically bound to TNF-α prevents TNF-α from inducing nitric
oxide production, thereby weakening the pro-inflammatory effect of TNF-α, and
inhibiting TNF-α-induced apoptosis. Liu et al. [148] screened an 28-nt RNA aptamer
for TNF-α, and constructed an electrochemical biosensor for detecting TNF-α in
human blood based on the aptamers.
In order to promote the potential of clinical transformation, new aptamers of
TNF-α have been continuously screened and identified. In 2019, Lai et al. [88]
screened a new aptamer aptTNF-α/aptTNF-α-PEG (K D = ∼8 nM) for TNF-α.
In a mice acute lung injury model, aptTNF-α/aptTNF-α-PEG reduced the degree
of lung injury induced by LPS and inhibited the expression of pro-inflammatory
cytokines/chemokines in lung tissue. Similarly, in the acute liver failure (ALF) model,
aptTNF-α/aptTNF-α-PEG not only reduced the degree of liver cell damage during
acute injury but also enhanced the early regeneration of liver tissue. In acute tissue
injury mediated by TNF-α, the duration of intervention is the key to successful inhibition of the TNF-α pathway. Compared with protein inhibitors, aptTNF-α/aptTNFα-PEG has a shorter and adjustable inhibition time. Therefore, this study also developed the complementary sequence of the aptamer as an antidote, enhancing the rapid
termination of aptamer antagonism when needed. Mashayekhi et al. [149] screened
novel DNA aptamers with TNF-α inhibitory activity, and linked T1 and T4 aptamers
to form an aptamer dimer through 10 dT linker sequences (Fig. 6.5). The dimer
aptamer can bind to hTNF-α and neutralize its activity. In the mice fibroblast cell
line (L929), the inhibition rate of the approved anti-TNF-α agent etanercept was
60%, while the inhibition rate of the aptamer dimer on hTNF-α reached 40%, indicating that the anti-hTNF-α aptamer dimer may become an alternative therapy for
restraining hTNF-α.
145
clinical development of mouse encephalitis was inhibited. Gene expression analysis
suggested that the expression of inflammatory genes including IL-23, IL-17, IL-6,
and INFgamma decreased. Lenn et al. [145] screened and optimized the 62 nt RNA
aptamer inhibitors of IL-23 and applied them in the local treatment of psoriasis.
The aptamer penetrated through the complete human skin barrier and entered the
epidermis and dermis to reach a therapeutic level, which can still target endogenous
IL-23 by maintaining its activity and biological conformation after skin penetration.
6.4.2 Aptamers Targeting Tumor Necrosis Factor (TNF)
6.4.2.1 TNF-α
TNF-α is a major pro-inflammatory cytokine and plays an important role in apoptosis,
cell proliferation, and immune response. TNF-α exerts pro-inflammatory or antiinflammatory effects by binding to type I (TNF-RI; p55) or type II (TNF-RII; p75)
receptors and activating different intracellular signal transduction pathways [146].
Orava et al. [147] screened a 25 nt TNF-α DNA aptamer VR11 with G-quadruplex
structure. VR11 specifically bound to TNF-α prevents TNF-α from inducing nitric
oxide production, thereby weakening the pro-inflammatory effect of TNF-α, and
inhibiting TNF-α-induced apoptosis. Liu et al. [148] screened an 28-nt RNA aptamer
for TNF-α, and constructed an electrochemical biosensor for detecting TNF-α in
human blood based on the aptamers.
In order to promote the potential of clinical transformation, new aptamers of
TNF-α have been continuously screened and identified. In 2019, Lai et al. [88]
screened a new aptamer aptTNF-α/aptTNF-α-PEG (K D = ∼8 nM) for TNF-α.
In a mice acute lung injury model, aptTNF-α/aptTNF-α-PEG reduced the degree
of lung injury induced by LPS and inhibited the expression of pro-inflammatory
cytokines/chemokines in lung tissue. Similarly, in the acute liver failure (ALF) model,
aptTNF-α/aptTNF-α-PEG not only reduced the degree of liver cell damage during
acute injury but also enhanced the early regeneration of liver tissue. In acute tissue
injury mediated by TNF-α, the duration of intervention is the key to successful inhibition of the TNF-α pathway. Compared with protein inhibitors, aptTNF-α/aptTNFα-PEG has a shorter and adjustable inhibition time. Therefore, this study also developed the complementary sequence of the aptamer as an antidote, enhancing the rapid
termination of aptamer antagonism when needed. Mashayekhi et al. [149] screened
novel DNA aptamers with TNF-α inhibitory activity, and linked T1 and T4 aptamers
to form an aptamer dimer through 10 dT linker sequences (Fig. 6.5). The dimer
aptamer can bind to hTNF-α and neutralize its activity. In the mice fibroblast cell
line (L929), the inhibition rate of the approved anti-TNF-α agent etanercept was
60%, while the inhibition rate of the aptamer dimer on hTNF-α reached 40%, indicating that the anti-hTNF-α aptamer dimer may become an alternative therapy for
restraining hTNF-α.