Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 776, Issue -, Pages 2-8Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2014.08.007
Keywords
Xeroderma pigmentosum; Gene therapy; Engineered nucleases; TALEN; UV light; Nucleotide excision repair
Funding
- Agence Nationale pour la Recherche Programme (Paris, France) [ANR-07-RIB-020-02]
- Association Francaise contre les Myopathies (Evry, France) [2008 No 12008]
- Association Nationale de la Recherche et de la Technologie (Paris)
- l' Association de Recherche sur le Cancer (Villejuif, France)
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Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients. (C) 2014 Elsevier B.V. All rights reserved.
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