RNA therapeutics silence a disease gene by binding its messenger RNA directly, either triggering enzymatic degradation (siRNA) or blocking translation, rather than acting on the protein the gene ultimately produces.
protein_output ~ mRNA_level * (1 - knockdown)
knockdown -> 1 as complementarity, RISC loading increase
- Oligonucleotide dose — the amount of siRNA or antisense oligonucleotide (ASO) delivered to the cell.
- mRNA target sites — the complementary sequence region on the disease-driving transcript targeted for silencing.
- Target complementarity — how precisely the oligonucleotide's sequence matches its intended mRNA target.
- Degradation (RISC) rate — how efficiently the RNA-induced silencing complex (or RNase H, for ASOs) cleaves the bound transcript.
Patisiran (siRNA) and inotersen (ASO) both treat hereditary transthyretin amyloidosis by exactly this mechanism — knocking down production of the misfolding TTR protein at the mRNA level rather than targeting the protein itself.