RNA therapeutics: beyond RNA interference and antisense oligonucleotides
Open accessAbstract
Here, we discuss three RNA-based therapeutic technologies exploiting various oligonucleotides that bind to RNA by base pairing in a sequence-specific manner yet have different mechanisms of action and effects. RNA interference and antisense oligonucleotides downregulate gene expression by inducing enzyme-dependent degradation of targeted mRNA. Steric-blocking oligonucleotides block the access of cellular machinery to pre-mRNA and mRNA without degrading the RNA. Through this mechanism, steric-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression. Moreover, they can be extensively chemically modified to acquire more drug-like properties. The ability of RNA-blocking oligonucleotides to restore gene function makes them best suited for the treatment of genetic disorders. Positive results from clinical trials for the treatment of Duchenne muscular dystrophy show that this technology is close to achieving its clinical potential.
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siRNA therapy is still hampered by delivery and cellular uptake issues, making this approach currently unrealistic.
“Unfortunately, siRNA therapy is still hampered by delivery and cellular uptake issues87, making this approach currently unrealistic.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [87]
A variety of RNA therapeutics have been developed for GARD therapies based on miRNA, siRNA, mRNA, lncRNA, and genome editing systems containing RNA components.
“To date, a variety of RNA therapeutics have been developed for GARD therapies based on the versatile family of RNA molecules, including microRNA (miRNA), small interfering RNA (siRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), and genome editing systems containing RNA components.[6, 9, 16]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [9]
RNA interference technology enables downregulation of disease-related genes and protein expression.
“For instance, RNA interference (RNAi) technology enables the downregulation of disease related genes and protein expression; mRNA mediates the expression and supplementation of therapeutic proteins; the CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.[6, 9, 11, 17–20]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [9]
mRNA mediates the expression and supplementation of therapeutic proteins.
“For instance, RNA interference (RNAi) technology enables the downregulation of disease related genes and protein expression; mRNA mediates the expression and supplementation of therapeutic proteins; the CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.[6, 9, 11, 17–20]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [9]
The CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.
“For instance, RNA interference (RNAi) technology enables the downregulation of disease related genes and protein expression; mRNA mediates the expression and supplementation of therapeutic proteins; the CRISPR gene editing system facilitates gene engineering in vivo or through cell engineering ex vivo.[6, 9, 11, 17–20]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [9]
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- Authors
- Kole, R., Krainer, A. R., & Altman, S.
- Affiliations
- Sarepta Therapeutics (United States) (US)
- Cold Spring Harbor Laboratory (US)
- Yale University (US)
- Corresponding author
- Kole, Ryszard
- Venue
- Nature Reviews Drug Discovery
- Published
- 2012-01-20
- Volume
- 11
- Issue
- 2
- Pages
- 125-140
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC4743652
- OpenAlex
- W2006167464
- Cited by
- 1,152
- References
- 109
- Citations by year
- 2026: 33 · 2025: 52 · 2024: 63 · 2023: 60 · 2022: 84 · 2021: 81 · 2020: 71 · 2019: 77 · 2018: 102 · 2017: 87 · 2016: 100 · 2015: 111 · 2014: 94 · 2013: 90 · 2012: 45
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- National Cancer Institute (P01CA013106)
- National Institute of General Medical Sciences (R37GM042699, R01GM042699)
- 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 Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- RNA therapeutics, RNA interference, antisense oligonucleotides, alternative splicing, gene downregulation, Duchenne muscular dystrophy, spinal muscular atrophy, beta-thalassemia, genetic disorders, pre-mRNA
- MeSH terms
- Animals, Anti-Bacterial Agents, Antiviral Agents, Humans, Myotonic Dystrophy, RNA, Messenger, Gene Expression, beta-Thalassemia, Alternative Splicing, Oligodeoxyribonucleotides, Antisense, Muscular Dystrophy, Duchenne, RNA Interference, RNA, Small Interfering, Phosphorothioate Oligonucleotides, Morpholinos
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