1. The chemical structure
ASO is single-stranded, and siRNA is double-stranded
2. Mechanism of action
• ASO either degrades target mRNA through RNase H, interferes mRNA function via steric effects or affects mRNA shearing, or acts on miRNA
• siRNA degrades mRNA primarily through RISC
3. The cellular space where the drug is exerted
RNase H is present in both cytoplasm and nucleus, allowing ASO to function in both compartments. However, RISC is only present in the cytoplasm, limiting siRNA’s action to this space.
4. Duration of action and whether it can be amplified
• RISC can repeatedly target mRNA; prolonging the effect of siRNA.
• The released sense strand of siRNA can be degraded or serve as a primer for dsRNA amplification via RNA-dependent RNA polymerase, using target mRNA as a template. Dicer processes dsRNA into siRNA, initiating an amplified RNAi cycle. As a result, the drug effect is amplified in a cascading manner.
• ASO generally exhibits higher toxicity compared to siRNA, particularly liver and kidney toxicity. ASO also poses a risk of thrombocytopenia, likely linked to its structure and mechanism of action.
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