ArticleHepatology (Baltimore, Md.)2011
Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk.
Article in Hepatology (Baltimore, Md.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 136 citations in OpenAlex.
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- Identification of hepatocyte-primed cholangiocytes in the homeostatic liver by in vivo lentiviral gene transfer to mice and non-human primates.Cell reports · 2025Article
- Comprehensive analysis of off-target and on-target effects resulting from liver-directed CRISPR-Cas9-mediated gene targeting with AAV vectors.Molecular therapy. Methods & clinical development · 2024Article
- Gene Therapy for Inherited Liver Disease: To Add or to Edit.International journal of molecular sciences · 2024Review
- GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice.EMBO molecular medicine · 2024Article
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- Current landscape of gene-editing technology in biomedicine: Applications, advantages, challenges, and perspectives.MedComm · 2022Review
- Editing T cell repertoire by thymic epithelial cell-directed gene transfer abrogates risk of type 1 diabetes development.Molecular therapy. Methods & clinical development · 2022Article
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- Protection is not always a good thing: The immune system's impact on gene therapy.Genetics and molecular biology · 2022Article
- Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza.Viruses · 2020Article
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- Immune Responses to Viral Gene Therapy Vectors.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
31 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 6 institutions in 5 countries.
Funding
Abstract
unlabelledLentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity.
conclusionIDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis.
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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.