Gene editing for the efficient correction of a recurrent COL7A1 mutation in recessive dystrophic epidermolysis bullosa keratinocytes
Clonal gene therapy protocols based on the precise manipulation of epidermal stem cells require highly efficient gene-editing molecular tools. We have combined adeno-associated virus (AAV)-mediated delivery of donor template DNA with transcription activator-like nucleases (TALE) expressed by adenovi...
Gespeichert in:
| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
5 April 2016
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| In: |
Molecular therapy. Nucleic Acids
Year: 2016, Jahrgang: 5 |
| ISSN: | 2162-2531 |
| DOI: | 10.1038/mtna.2016.19 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.1038/mtna.2016.19 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S216225311730032X 
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| Verfasserangaben: | Cristina Chamorro, Angeles Mencía, David Almarza, Blanca Duarte, Hildegard Büning, Jessica Sallach, Ingrid Hausser, Marcela Del Río, Fernando Larcher and Rodolfo Murillas |
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| 245 | 1 | 0 | |a Gene editing for the efficient correction of a recurrent COL7A1 mutation in recessive dystrophic epidermolysis bullosa keratinocytes |c Cristina Chamorro, Angeles Mencía, David Almarza, Blanca Duarte, Hildegard Büning, Jessica Sallach, Ingrid Hausser, Marcela Del Río, Fernando Larcher and Rodolfo Murillas |
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| 520 | |a Clonal gene therapy protocols based on the precise manipulation of epidermal stem cells require highly efficient gene-editing molecular tools. We have combined adeno-associated virus (AAV)-mediated delivery of donor template DNA with transcription activator-like nucleases (TALE) expressed by adenoviral vectors to address the correction of the c.6527insC mutation in the COL7A1 gene, causing recessive dystrophic epidermolysis bullosa in a high percentage of Spanish patients. After transduction with these viral vectors, high frequencies of homology-directed repair were found in clones of keratinocytes derived from a recessive dystrophic epidermolysis bullosa (RDEB) patient homozygous for the c.6527insC mutation. Gene-edited clones recovered the expression of the COL7A1 transcript and collagen VII protein at physiological levels. In addition, treatment of patient keratinocytes with TALE nucleases in the absence of a donor template DNA resulted in nonhomologous end joining (NHEJ)-mediated indel generation in the vicinity of the c.6527insC mutation site in a large proportion of keratinocyte clones. A subset of these indels restored the reading frame of COL7A1 and resulted in abundant, supraphysiological expression levels of mutant or truncated collagen VII protein. Keratinocyte clones corrected both by homology-directed repair (HDR) or NHEJ were used to regenerate skin displaying collagen VII in the dermo-epidermal junction. | ||
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