Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Sep;16(9):543-52.
doi: 10.1038/nrg3978.

Knocking down disease: a progress report on siRNA therapeutics

Anders Wittrup  1 , Judy Lieberman  2
Affiliations
Review

Knocking down disease: a progress report on siRNA therapeutics

Anders Wittrup et al. Nat Rev Genet. 2015 Sep.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests statement

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

Figures

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.
See this image and copyright information in PMC

References

    1. Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc. Natl Acad. Sci. USA. 1978;75:280–284. - PMC - PubMed

    1. Stephenson ML, Zamecnik PC. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc. Natl Acad. Sci. USA. 1978;75:285–288. First demonstration of the possibility of inhibiting gene expression using oligonucleotides.

    1. Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 2012;11:125–140. - PMC - PubMed
    1. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 2010;50:259–293. - PubMed
    1. Sharma VK, Sharma RK, Singh SK. Antisense oligonucleotides: modifications and clinical trials. Med. Chem. Commun. 2014;5:1454–1471.

Publication types

Substances