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Título

Self-inactivating MLV vectors have a reduced genotoxic profile in human epidermal keratinocytes

Autor Larcher, Fernando; Mavilio, Fulvio
Palabras clave Retroviral integration
Insertional mutagenesis
Epidermolysis bullosa
Fecha de publicación 2013
EditorNature Publishing Group
Citación Gene Therapy 20: 949-957 (2013)
ResumenTransplantation of epithelia derived from keratinocyte stem cells transduced by retroviral vectors is a potential therapy for epidermolysis bullosa (EB), a family of inherited skin adhesion defects. The biosafety characteristics of retroviral vectors in keratinocytes are, however, poorly defined. We developed self-inactivating (SIN) vectors derived from the Moloney murine leukemia (MLV) and the human immunodeficiency (HIV) viruses expressing therapeutic levels of LAMB3, a transgene defective in junctional EB, and tested their integration profile in human primary keratinocytes. The SIN–HIV vector showed the expected preference for transcribed genes while the SIN–MLV vector integrated preferentially in regulatory elements, but showed a significantly lower tendency to target cell growth-related genes, transcription start sites and epigenetically defined promoters compared with a wild-type MLV vector in an epithelial cell context. A quantitative gene expression assay in individual keratinocyte clones showed that MLV-derived vectors deregulate expression of targeted genes at a lower frequency than in hematopoietic cells, and that the SIN–MLV design has the lowest activity compared to both MLV and SIN–HIV vectors. This study indicates that SIN–MLV vectors may have a better safety profile in keratinocyte than in hematopoietic cells, and be a reasonable alternative to lentiviral vectors for gene therapy of inherited skin disorders.
Descripción et al.
Versión del editorhttp://dx.doi.org/10.1038/gt.2013.18
URI http://hdl.handle.net/10261/111639
DOI10.1038/gt.2013.18
ISSN0969-7128
E-ISSN1476-5462
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