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

Itai M. Pessach, Luigi D. Notarangelo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1344-1350
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number6
StatePublished - Jun 2011
Externally publishedYes


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


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