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
. 2021 Jul:189:114432.
doi: 10.1016/j.bcp.2021.114432. Epub 2021 Jan 26.

The growth of siRNA-based therapeutics: Updated clinical studies

M May Zhang  1 , Raman Bahal  1 , Theodore P Rasmussen  1 , José E Manautou  1 , Xiao-Bo Zhong  2
Affiliations
Review

The growth of siRNA-based therapeutics: Updated clinical studies

M May Zhang et al. Biochem Pharmacol. 2021 Jul.

Abstract

More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.

Keywords: Clinical trial; Drug development; FDA approval; siRNAs.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

The authors declare that there are no conflicts of interest.

Figures

Figure 1.
Figure 1.
A summary of development of siRNA-based drugs with either FDA approval or in late phase 3 clinical trials.
Figure 2:
Figure 2:
A summary of chemical modifications in backbone and sugar and delivery platforms of the siRNA drugs.
See this image and copyright information in PMC

References

    1. Kim D and Rossi J, RNAi mechanisms and applications. Biotechniques, 2008. 44(5): p. 613–6. - PMC - PubMed
    1. Ozcan G, et al., Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev, 2015. 87: p. 108–19. - PMC - PubMed
    1. Fire A, et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 1998. 391(6669): p. 806–11. - PubMed
    1. Setten RL, Rossi JJ, and Han SP, The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov, 2019. 18(6): p. 421–446. - PubMed
    1. Frazer KA, Decoding the human genome. Genome Res, 2012. 22(9): p. 1599–601. - PMC - PubMed

Publication types

MeSH terms