RNA-Targeted Therapeutics
Open accessAbstract
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
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Olezarsen is an investigational GalNAc3-conjugated antisense oligonucleotide that reduces apolipoprotein C-III production by binding to APOC3 mRNA and inducing its degradation through ribonuclease H1-mediated cleavage of the sense strand.
“Olezarsen is an investigational GalNAc 3 -conjugated antisense oligonucleotide that reduces apolipoprotein C-III production by binding to APOC3 mRNA and inducing its degradation through ribonuclease H1-mediated cleavage of the sense strand. 26,28,29”
From Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome (2024) · cites this paper as [26]
Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III.
“Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III.”
From Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome (2024) · cites this paper as [26]
RNA-based therapeutics regulate undruggable proteins at the genetic/transcription level via Watson-Crick complementary binding, broadening the range of druggable targets.
“RNA-based therapeutics have proven to be a stunning approach to regulate “undruggable” proteins at the genetic/transcription level, driven by the Watson-Crick complementary rule of binding, which has broadened the range of druggable targets.553”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [553]
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References 186 · Cited by 841
- Authors
- Crooke, S. T., Witztum, J. L., Bennett, C. F., & Baker, B. F.
- Affiliations
- Ionis Pharmaceuticals (United States) (US)
- University of California San Diego (US)
- Corresponding author
- Crooke, Stanley T.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 27
- Issue
- 4
- Pages
- 714-739
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2795531081
- Cited by
- 841
- References
- 186
- Citations by year
- 2026: 96 · 2025: 91 · 2024: 107 · 2023: 95 · 2022: 120 · 2021: 120 · 2020: 99 · 2019: 86 · 2018: 25
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-02-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ionis Pharmaceuticals, Inc
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- RNA-targeted therapeutics, modified oligonucleotides, Watson-Crick base pairing, antisense oligonucleotides, spinal muscular atrophy, LDL cholesterol lowering, intrathecal drug delivery, intravitreal delivery, subcutaneous delivery, undruggable targets, drug discovery, mechanism of action
- MeSH terms
- Animals, Humans, Muscular Atrophy, Spinal, Genetic Therapy, Oligoribonucleotides, Antisense, RNA, Small Interfering, Drug Discovery, Molecular Targeted Therapy
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