Self-inactivating MLV vectors have a reduced genotoxic profile in human epidermal keratinocytes.
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| Abstract |
Transplantation 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.
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| Authors | A Cavazza, F Cocchiarella, C Bartholomae, M Schmidt, C Pincelli, F Larcher, F Mavilio |
| Journal | Gene therapy (Gene Ther) Vol. 20 Issue 9 Pg. 949-57 (Sep 2013) ISSN: 1476-5462 [Electronic] England |
| PMID | 23615186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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