ArticleNature medicine2016
RNA interference-induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- RNA interference in the era of nucleic acid therapeutics.Nature biotechnology · 2024Review
- Evaluation of on- and off-target effects of self-assembled epidermal growth factor receptor small interfering RNA delivery system.Clinical and translational medicine · 2024Article
- RNA-Based Therapeutic Technology.International journal of molecular sciences · 2023Review
- Reassessment of miRNA variant (isomiRs) composition by small RNA sequencing.Cell reports methods · 2023Article
- miRNA Pathway Alteration in Response to Non-Coding RNA Delivery in Viral Vector-Based Gene Therapy.International journal of molecular sciences · 2022Review
- Identification of New Toxicity Mechanisms in Drug-Induced Liver Injury through Systems Pharmacology.Genes · 2022Article
- PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications.Nature cell biology · 2021Article
- Characterization of the microRNA Expression Profiles in the Goat Kid Liver.Frontiers in genetics · 2021Article
- Physical and chemical template-blocking strategies in the exponential amplification reaction of circulating microRNAs.Analytical and bioanalytical chemistry · 2020Article
- Endogenous MicroRNA Competition as a Mechanism of shRNA-Induced Cardiotoxicity.Molecular therapy. Nucleic acids · 2020Article
- ProphylacticCancer research · 2020Article
- Identification of miR-146a is Associated with the Aggressiveness and Suppresses Proliferation via Targeting CDKN2A in Breast Cancer.Pathology oncology research : POR · 2020Article
- A Complete Pipeline for Isolating and Sequencing MicroRNAs, and Analyzing Them Using Open Source Tools.Journal of visualized experiments : JoVE · 2019Article
- Deletion of miR-126a Promotes Hepatic Aging and Inflammation in a Mouse Model of Cholestasis.Molecular therapy. Nucleic acids · 2019Article
- Liver Cancer Gene Discovery Using Gene Targeting, Sleeping Beauty, and CRISPR/Cas9.Seminars in liver disease · 2019Review
- Application of Locked Nucleic Acid Oligonucleotides for siRNA Preclinical Bioanalytics.Scientific reports · 2019Article
- miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression.Nature communications · 2018Article
- Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.Nature communications · 2018Article
- Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin.Molecular therapy. Nucleic acids · 2017Article
- Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.Human gene therapy · 2017Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Small RNAs can be engineered to target and eliminate expression of disease-causing genes or infectious viruses, resulting in the preclinical and clinical development of RNA interference (RNAi) therapeutics using these small RNAs. To ensure the success of RNAi therapeutics, small hairpin RNAs (shRNAs) must co-opt sufficient quantities of the endogenous microRNA machinery to elicit efficient gene knockdown without impeding normal cellular function. We previously observed liver toxicity-including hepatocyte turnover, loss of gene repression and lethality-in mice receiving high doses of a recombinant adeno-associated virus (rAAV) vector expressing shRNAs (rAAV-shRNAs); however the mechanism by which toxicity ensues has not been elucidated. Using rAAV-shRNAs we have now determined that hepatotoxicity arises when exogenous shRNAs exceed 12% of the total amount of liver microRNAs. After this threshold was surpassed, shRNAs specifically reduced the initially synthesized 22-nucleotide isoform of microRNA (miR)-122-5p without substantially affecting other microRNAs, resulting in functional de-repression of miR-122 target mRNAs. Delivery of a rAAV-shRNA vector expressing mature miR-122-5p could circumvent toxicity, despite the exogenous shRNA accounting for 70% of microRNAs. Toxicity was also not observed in Mir122-knockout mice regardless of the level or sequence of the shRNA. Our study establishes limits to the microRNA machinery that is available for therapeutic siRNAs and suggests new paradigms for the role of miR-122 in liver homeostasis in mice.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.