ArticleMolecular therapy : the journal of the American Society of Gene Therapy2012
Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Gene Therapy Advances: A Meta-Analysis of AAV Usage in Clinical Settings.Frontiers in medicine · 2021Pooled it
- Immunogenicity of Gene and Cell Therapies.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy.Molecular therapy. Methods & clinical development · 2025Article
- Inactivity-induced phrenic motor facilitation requires PKCζ activity within phrenic motor neurons.Journal of neurophysiology · 2024Article
- Ex vivo and in vivo suppression of SARS-CoV-2 with combinatorial AAV/RNAi expression vectors.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Delivery of pDNA to the Lung by Lipopolyplexes UsingPharmaceutics · 2021Article
- BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy.Molecular therapy. Nucleic acids · 2021Article
- Article
- Comprehensive analysis of drugs to treat SARS‑CoV‑2 infection: Mechanistic insights into current COVID‑19 therapies (Review).International journal of molecular medicine · 2020Review
- Review
- Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.Molecular therapy. Methods & clinical development · 2018Article
- Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs.Molecular therapy. Nucleic acids · 2017Article
- Expression of short hairpin RNAs using the compact architecture of retroviral microRNA genes.Nucleic acids research · 2017Article
- Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.Human gene therapy · 2017Article
- TALEN/CRISPR-mediated engineering of a promoterless anti-viral RNAi hairpin into an endogenous miRNA locus.Nucleic acids research · 2017Article
- Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA.EMBO molecular medicine · 2016Article
- Combinations of siRNAs against La Autoantigen with NS5B or hVAP-A Have Additive Effect on Inhibition of HCV Replication.Hepatitis research and treatment · 2016Article
- Combinatorial RNA Interference Therapy Prevents Selection of Pre-existing HBV Variants in Human Liver Chimeric Mice.Scientific reports · 2015Article
- Recombinant AAV as a platform for translating the therapeutic potential of RNA interference.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Review
- Deep Sequencing Insights in Therapeutic shRNA Processing and siRNA Target Cleavage Precision.Molecular therapy. Nucleic acids · 2014Article
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21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hepatitis C virus (HCV) chronically infects 2% of the world population and effective treatment is limited by long duration and significant side-effects. Here, we describe a novel drug, intended as a "single-shot " therapy, which expresses three short hairpin RNAs (shRNAs) that simultaneously target multiple conserved regions of the HCV genome as confirmed in vitro by knockdown of an HCV replicon system. Using a recombinant adeno-associated virus (AAV) serotype 8 vector for delivery, comprehensive transduction of hepatocytes was achieved in vivo in a nonhuman primate (NHP) model following a single intravenous injection. However, dose ranging studies performed in 13 NHP resulted in high-expression levels of shRNA from wild-type (wt) Pol III promoters and dose-dependent hepatocellular toxicity, the first demonstration of shRNA-related toxicity in primates, establishing that the hepatotoxicity arises from highly conserved features of the RNA interference (RNAi) pathway. In the second generation drug, each promoter was re-engineered to reduce shRNA transcription to levels that circumvent toxicity but still inhibit replicon activity. In vivo testing of this modified construct in 18 NHPs showed conservation of hepatocyte transduction but complete elimination of hepatotoxicity, even with sustained shRNA expression for 50 days. These data support progression to a clinical study for treatment of HCV infection.
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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.