期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 127, 期 6, 页码 1344-1350出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.02.027
关键词
Primary immunodeficiencies; severe combined immunodeficiency; gene therapy; gene correction; locus-specific targeting; homing endonucleases; meganucleases; zinc finger nucleases; safe harbors; transposons
资金
- National Institutes of Health [1R03AI088352-01, 1R21AI089810-01]
- March of Dimes [6-FY10-282]
- Manton Foundation
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies (PIDs). For patients lacking an HLA-identical donor, gene therapy is an attractive therapeutic option. Approaches based on insertion of a functional gene by using viral vectors have provided proof of concept for the ability of gene therapy to cure PIDs. However, leukemic transformation as a result of insertional mutagenesis has been observed, prompting development of novel approaches based on introduction of DNA double-strand breaks into the endogenous locus to achieve gene correction, or into a safe genomic location (safe harbor). Homing endonucleases and zinc finger nucleases are target-specific endonucleases that induce site-specific DNA double-strand breaks, facilitating homologous recombination around their target sites to achieve gene correction or gene insertion into safe harbors. An alternative approach to achieve site-specific insertion of functional genes is based on transposons, DNA elements that spontaneously translocate from a specific chromosomal location to another. These novel tools may lead to efficient and safer strategies to achieve gene therapy for PIDs and other disorders. (J Allergy Clin Immunol 2011;127:1344-50.)
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