ArticlePloS one2016
Towards a Safer, More Randomized Lentiviral Vector Integration Profile Exploring Artificial LEDGF Chimeras.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Precise progerin targeting using RfxCas13d: A therapeutic avenue for Hutchinson-Gilford progeria syndrome.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Advances in HIV Gene Therapy.International journal of molecular sciences · 2024Review
- Scalable manufacturing of gene-modified human mesenchymal stromal cells with microcarriers in spinner flasks.Applied microbiology and biotechnology · 2023Article
- Directing iPSC differentiation into iTenocytes using combined scleraxis overexpression and cyclic loading.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2023Article
- Review
- In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.Nature communications · 2022Article
- Using Inhibitory DREADDs to Silence LC Neurons in Monkeys.Brain sciences · 2022Article
- Review
- Context-aware synthetic biology by controller design: Engineering the mammalian cell.Cell systems · 2021Review
- Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies.Frontiers in cellular neuroscience · 2021Review
- Gene Editing and Genotoxicity: Targeting the Off-Targets.Frontiers in genome editing · 2020Review
- Shifting Retroviral Vector Integrations Away from Transcriptional Start Sites via DNA-Binding Protein Domain Insertion into Integrase.Molecular therapy. Methods & clinical development · 2019Article
- Cellular and molecular mechanisms of HIV-1 integration targeting.Cellular and molecular life sciences : CMLS · 2018Review
- Engineering Next-Generation BET-Independent MLV Vectors for Safer Gene Therapy.Molecular therapy. Nucleic acids · 2017Article
- Prolonged Integration Site Selection of a Lentiviral Vector in the Genome of Human Keratinocytes.Medical science monitor : international medical journal of experimental and clinical research · 2017Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The capacity to integrate transgenes into the host cell genome makes retroviral vectors an interesting tool for gene therapy. Although stable insertion resulted in successful correction of several monogenic disorders, it also accounts for insertional mutagenesis, a major setback in otherwise successful clinical gene therapy trials due to leukemia development in a subset of treated patients. Despite improvements in vector design, their use is still not risk-free. Lentiviral vector (LV) integration is directed into active transcription units by LEDGF/p75, a host-cell protein co-opted by the viral integrase. We engineered LEDGF/p75-based hybrid tethers in an effort to elicit a more random integration pattern to increase biosafety, and potentially reduce proto-oncogene activation. We therefore truncated LEDGF/p75 by deleting the N-terminal chromatin-reading PWWP-domain, and replaced this domain with alternative pan-chromatin binding peptides. Expression of these LEDGF-hybrids in LEDGF-depleted cells efficiently rescued LV transduction and resulted in LV integrations that distributed more randomly throughout the host-cell genome. In addition, when considering safe harbor criteria, LV integration sites for these LEDGF-hybrids distributed more safely compared to LEDGF/p75-mediated integration in wild-type cells. This approach should be broadly applicable to introduce therapeutic or suicide genes for cell therapy, such as patient-specific iPS cells.
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