The current state and future directions of RNAi-based therapeutics
Abstract
The RNA interference (RNAi) pathway regulates mRNA stability and translation in nearly all human cells. Small double-stranded RNA molecules can efficiently trigger RNAi silencing of specific genes, but their therapeutic use has faced numerous challenges involving safety and potency. However, August 2018 marked a new era for the field, with the US Food and Drug Administration approving patisiran, the first RNAi-based drug. In this Review, we discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, the state of the current clinical pipeline and prospects for future advances, including novel RNAi pathway agents utilizing mechanisms beyond post-translational RNAi silencing.
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RNA interference therapeutics utilize an endogenous mechanism whereby short interfering RNAs direct the RNA-induced silencing complex to target gene transcripts, resulting in sequence-specific catalytic RNA cleavage and subsequent lowering of the target protein.
“RNA interference (RNAi) therapeutics utilize an endogenous mechanism whereby short interfering RNAs (siRNAs) direct the RNA-induced silencing complex (RISC) to target gene transcripts, resulting in a sequence-speci c and catalytic RNA cleavage and subsequent lowering of the target protein 1 .”
From Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates (2022) · cites this paper as [1]
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- Authors
- Setten, R. L., Rossi, J. J., & Han, S.-P.
- Affiliations
- City Of Hope National Medical Center (US)
- California Institute of Technology (US)
- Venue
- Nature Reviews Drug Discovery
- Published
- 2019-03-07
- Volume
- 18
- Issue
- 6
- Pages
- 421-446
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2920438880
- Cited by
- 1,443
- References
- 18
- Citations by year
- 2026: 154 · 2025: 175 · 2024: 223 · 2023: 215 · 2022: 222 · 2021: 235 · 2020: 176 · 2019: 42
- FWCI
- 14.83
- Type
- journal article
- Language
- en
- Update notices
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- RNA interference, RNAi therapeutics, patisiran, FDA approval, gene silencing, mRNA stability
- MeSH terms
- RNAi Therapeutics, Animals, Clinical Trials as Topic, Humans, Drug Delivery Systems, RNA Interference, RNA, Small Interfering
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