2026-04-28T21:35:06Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/67432025-05-08T10:07:16Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Sánchez-Hernández, Sabina
author
Gutierrez-Guerrero, Alejandra
author
Martín-Guerra, Rocío
author
Cortijo-Gutierrez, Marina
author
Tristán-Manzano, María
author
Rodriguez Perales, Sandra
author
Sánchez, Laura
author
Garcia-Perez, Jose Luis
author
Chato-Astrain, Jesus
author
Fernandez-Valades, Ricardo
author
Carrillo-Galvez, Ana Belén
author
Anderson, Per
author
Montes, Rosa
author
Real, Pedro J
author
Martin, Francisco
author
Benabdellah, Karim
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Ministerio de Ciencia e Innovación (España)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
2018-11-29T12:38:36Z
2018-11-29T12:38:36Z
2018-08-18
Mol Ther Nucleic Acids. 2018;13:16-28.
2162-2531
http://hdl.handle.net/20.500.12105/6743
30227274
10.1016/j.omtn.2018.08.007
Molecular therapy. Nucleic acids
Integration-defective lentiviral vectors (IDLVs) have become an important alternative tool for gene therapy applications and basic research. Unfortunately, IDLVs show lower transgene expression as compared to their integrating counterparts. In this study, we aimed to improve the expression levels of IDLVs by inserting the IS2 element, which harbors SARs and HS4 sequences, into their LTRs (SE-IS2-IDLVs). Contrary to our expectations, the presence of the IS2 element did not abrogate epigenetic silencing by histone deacetylases. In addition, the IS2 element reduced episome levels in IDLV-transduced cells. Interestingly, despite these negative effects, SE-IS2-IDLVs outperformed SE-IDLVs in terms of percentage and expression levels of the transgene in several cell lines, including neurons, neuronal progenitor cells, and induced pluripotent stem cells. We estimated that the IS2 element enhances the transcriptional activity of IDLV LTR circles 6- to 7-fold. The final effect the IS2 element in IDLVs will greatly depend on the target cell and the balance between the negative versus the positive effects of the IS2 element in each cell type. The better performance of SE-IS2-IDLVs was not due to improved stability or differences in the proportions of 1-LTR versus 2-LTR circles but probably to a re-positioning of IS2-episomes into transcriptionally active regions.
eng
HS4 insulator
IDLV
Gene therapy
Lentiviral vector
Scaffold or matrix attachment regions
The IS2 Element Improves Transcription Efficiency of Integration-Deficient Lentiviral Vector Episomes
journal article
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theIS2elementimproves_2018.pdf.txt
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