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, 16 (9), 543-52

Knocking Down Disease: A Progress Report on siRNA Therapeutics


Knocking Down Disease: A Progress Report on siRNA Therapeutics

Anders Wittrup et al. Nat Rev Genet.


Small interfering RNAs (siRNAs), which downregulate gene expression guided by sequence complementarity, can be used therapeutically to block the synthesis of disease-causing proteins. The main obstacle to siRNA drugs - their delivery into the target cell cytosol - has been overcome to allow suppression of liver gene expression. Here, we review the results of recent clinical trials of siRNA therapeutics, which show efficient and durable gene knockdown in the liver, with signs of promising clinical outcomes and little toxicity. We also discuss the barriers to more widespread applications that target tissues besides the liver and the most promising avenues to overcome them.

Conflict of interest statement

Competing interests statement

The authors declare competing interests: see Web version for details.


Figure 1
Figure 1. Mechanism of gene knockdown by siRNAs
Exogenously administered small interfering RNAs (siRNAs; double-stranded ~22-nucleotide-long RNA molecules with 2-nucleotide overhangs at the 3´ ends) exploit the endogenous RNA interference (RNAi) machinery. In the endogenous pathway, Dicer generates microRNAs (miRNAs) from RNA hairpins encoded by miRNA genes. The Dicer machinery also processes exogenous double-stranded RNA (dsRNA) sequences containing loops called short hairpin RNAs (shRNAs). Synthetic siRNAs bypass Dicer processing and can directly associate with the RNA-induced silencing complex (RISC) to mediate recognition of target mRNAs through base-pair complementarity. Argonaute 2 in the RISC complex then enzymatically cleaves the target mRNA, leading to target gene knockdown.

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