transient expression of an ledgf/p75 chimera retargets lentivector integration and functionally rescues in a model for x-cgd

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ID: 215524
2013
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Abstract
Retrovirus-based vectors are commonly used as delivery vehicles to correct genetic diseases because of their ability to integrate new sequences stably. However, adverse events in which vector integration activates proto-oncogenes, leading to clonal expansion and leukemogenesis hamper their application. The host cell-encoded lens epithelium-derived growth factor (LEDGF/p75) binds lentiviral integrase and targets integration to active transcription units. We demonstrated earlier that replacing the LEDGF/p75 chromatin interaction domain with an alternative DNA-binding protein could retarget integration. Here, we show that transient expression of the chimeric protein using mRNA electroporation efficiently redirects lentiviral vector (LV) integration in wild-type (WT) cells. We then employed this technology in a model for X-linked chronic granulomatous disease (X-CGD) using myelomonocytic PLB-985 gp91−/− cells. Following electroporation with mRNA encoding the LEDGF-chimera, the cells were treated with a therapeutic lentivector encoding gp91phox. Integration site analysis revealed retargeted integration away from genes and towards heterochromatin-binding protein 1β (CBX1)-binding sites, in regions enriched in marks associated with gene silencing. Nevertheless, gp91phox expression was stable for at least 6 months after electroporation and NADPH-oxidase activity was restored to normal levels as determined by superoxide production. Together, these data provide proof-of-principle that transient expression of engineered LEDGF-chimera can retarget lentivector integration and rescues the disease phenotype in a cell model, opening perspectives for safer gene therapy.
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vets2013moleculartransient Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Sofie Vets, Jan De Rijck, Christian Brendel, Manuel Grez, Frederic Bushman, Zeger Debyser, Rik Gijsbers
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Journal coordination chemistry reviews
Year 2013
DOI
10.1038/mtna.2013.4
URL
http://www.sciencedirect.com/science/article/pii/S2162253116301378
Keywords
gene therapy pharmacology

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