ArticleNucleic acids research2020
Some ASOs that bind in the coding region of mRNAs and induce RNase H1 cleavage can cause increases in the pre-mRNAs that may blunt total activity.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
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- Multisystem Symptoms in Myotonic Dystrophy Type 1: A Management and Therapeutic Perspective.International journal of molecular sciences · 2025Review
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- Emerging RNAi Therapies to Treat Hypertension.Molecular diagnosis & therapy · 2025Review
- Exploratory Studies on RNAi-Based Therapies Targeting Angiotensinogen in Hypertension: Scoping Review.Journal of personalized medicine · 2024Review
- Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.PLoS genetics · 2024Article
- The promise of RNA-based therapeutics in revolutionizing heart failure management - a narrative review of current evidence.Annals of medicine and surgery (2012) · 2023Review
- Chemistry of Therapeutic Oligonucleotides That Drives Interactions with Biomolecules.Pharmaceutics · 2022Review
- RNA modifications can affect RNase H1-mediated PS-ASO activity.Molecular therapy. Nucleic acids · 2022Article
- FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?Journal of personalized medicine · 2022Review
- LNA oligonucleotide mediates an anti-inflammatory effect in autoimmune myocarditis via targeting lactate dehydrogenase B.Immunology · 2022Article
- The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery.Biomedicines · 2021Review
- Antisense technology: A review.The Journal of biological chemistryReview
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antisense oligonucleotide (ASO) drugs that trigger RNase H1 cleavage of target RNAs have been developed to treat various diseases. Basic pharmacological principles suggest that the development of tolerance is a common response to pharmacological interventions. In this manuscript, for the first time we report a molecular mechanism of tolerance that occurs with some ASOs. Two observations stimulated our interest: some RNA targets are difficult to reduce with RNase H1 activating ASOs and some ASOs display a shorter duration of activity than the prolonged target reduction typically observed. We found that certain ASOs targeting the coding region of some mRNAs that initially reduce target mRNAs can surprisingly increase the levels of the corresponding pre-mRNAs. The increase in pre-mRNA is delayed and due to enhanced transcription and likely also slower processing. This process requires that the ASOs bind in the coding region and reduce the target mRNA by RNase H1 while the mRNA resides in the ribosomes. The pre-mRNA increase is dependent on UPF3A and independent of the NMD pathway or the XRN1-CNOT pathway. The response is consistent in multiple cell lines and independent of the methods used to introduce ASOs into cells.
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