title: Gene therapy for primary immunodeficiencies: looking ahead, toward gene correction.
abstract: 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.
authors: Department of Pediatric Critical Care and Talpiot Medical Leadership Program, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors: Itai M
authors: IM
authors: Pessach
authors: Luigi D
authors: LD
authors: Notarangelo
mesh_terms: D004251:DNA Transposable Elements / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods / Q000639:trends*; D005822:Genetic Vectors; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008957:Models, Genetic; D052416:Targeted Gene Repair / Q000379:methods / Q000639:trends; D019895:Transposases / Q000235:genetics; D014780:Viruses / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; D019895:Transposases; D004720:Endonucleases