ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 67 citations in OpenAlex.
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- CROPseq-multi: a universal solution for multiplexed perturbation in high-content pooled CRISPR screens.bioRxiv : the preprint server for biology · 2025Article
- Preclinical efficacy of a modified gamma-globin lentivirus gene therapy in Berkeley sickle cell anemia mice and human xenograft models.Molecular therapy. Methods & clinical development · 2025Article
- Enhancing lentiviral production for WAS gene therapy: a comparative analysis of stable producer cell lines evaluating flatware system and adherent bioreactors in perfusion mode.Frontiers in bioengineering and biotechnology · 2025Article
- An optimized protocol for quality control of gene therapy vectors using nanopore direct RNA sequencing.Genome research · 2024Article
- Leveraging a self-cleaving peptide for tailored control in proximity labeling proteomics.Cell reports methods · 2024Article
- Lentiviral vectors for inducible, transactivator-free advanced therapy medicinal products: Application to CAR-T cells.Molecular therapy. Nucleic acids · 2023Article
- The sound of silence: Transgene silencing in mammalian cell engineering.Cell systems · 2022Review
- CRISPR-Based Tools for Fighting Rare Diseases.Life (Basel, Switzerland) · 2022Review
- Differential CXCR4 expression on hematopoietic progenitor cells versus stem cells directs homing and engraftment.JCI insight · 2022Article
- Investigating the Barrier Activity of Novel, Human Enhancer-Blocking Chromatin Insulators for Hematopoietic Stem Cell Gene Therapy.Human gene therapy · 2021Article
- Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Improved Functionality of Integration-Deficient Lentiviral Vectors (IDLVs) by the Inclusion of ISPharmaceutics · 2021Article
- The Promise and the Hope of Gene Therapy.Frontiers in genome editing · 2021Review
- 'Mini' U6 Pol III promoter exhibits nucleosome redundancy and supports multiplexed coupling of CRISPR/Cas9 effects.Gene therapy · 2020Article
- Gene Therapy For Beta-Thalassemia: Updated Perspectives.The application of clinical genetics · 2019Article
- The IS2 Element Improves Transcription Efficiency of Integration-Deficient Lentiviral Vector Episomes.Molecular therapy. Nucleic acids · 2018Article
- Detailed comparison of retroviral vectors and promoter configurations for stable and high transgene expression in human induced pluripotent stem cells.Gene therapy · 2017Article
- Optimizing autologous cell grafts to improve stem cell gene therapy.Experimental hematology · 2016Review
- Insulated Foamy Viral Vectors.Human gene therapy · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Self-inactivating (SIN) lentiviruses flanked by the 1.2-kb chicken hypersensitive site-4 (cHS4) insulator element provide consistent, improved expression of transgenes, but have significantly lower titers. The mechanism by which this occurs is unknown. Lengthening the lentiviral (LV) vector transgene cassette by an additional 1.2 kb by an internal cassette caused no further reduction in titers. However, when cHS4 sequences or inert DNA spacers of increasing size were placed in the 3'-long terminal repeat (LTR), infectious titers decreased proportional to the length of the insert. The stage of vector life cycle affected by vectors carrying the large cHS4 3'LTR insert was compared to a control vector: there was no increase in read-through transcription with insertion of the 1.2-kb cHS4 in the 3'LTR. Equal amount of full-length viral mRNA was produced in packaging cells and viral assembly/packaging was unaffected, resulting in comparable amounts of intact vector particles produced by either vectors. However, LV vectors carrying cHS4 in the 3'LTR were inefficiently processed following target-cell entry, with reduced reverse transcription and integration efficiency, and hence lower transduction titers. Therefore, vectors with large insertions in the 3'LTR are transcribed and packaged efficiently, but the LTR insert hinders viral-RNA (vRNA) processing and transduction of target cells. These studies have important implications in design of integrating vectors.
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Registered trials
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