Gene therapy for primary immunodeficiencies: Looking ahead, toward gene correction

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:127

Article

Pessach, Itai M.^1,2,3  Notarangelo, Luigi D.^3,4 

[1] Safra Childrens Hosp, Sheba Med Ctr, Dept Pediat Crit Care, Tel Hashomer, Israel

[2] Safra Childrens Hosp, Sheba Med Ctr, Talpiot Med Leadership Program, Tel Hashomer, Israel

[3] Harvard Univ, Sch Med, Div Immunol, Boston, MA USA

[4] Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA

关键词: Primary immunodeficiencies;    severe combined immunodeficiency;    gene therapy;    gene correction;    locus-specific targeting;    homing endonucleases;    meganucleases;    zinc finger nucleases;    safe harbors;    transposons;   

DOI  :  10.1016/j.jaci.2011.02.027

来源: Elsevier

【 摘 要 】

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.)

【 授权许可】

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