New approaches to gene therapy for primary immunodeficiencies

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies (PIDD). However, many patients lack an HLA-identical donor. For that group, gene therapy may be a therapeutic option.

Gene insertion by viral vectors has provided proof of concept for PIDD cure. However, leukemic transformation due to insertional mutagenesis has tampered the initial optimism.

Primary immunodeficiency disorders (PIDD) (click to enlarge the image)

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

DNA double-strand breaks

New approaches are based on introduction of DNA double-strand breaks into:

- the endogenous locus to achieve gene correction
- a safe genomic location ("safe harbor")

Target-specific endonucleases that induce site-specific DNA double-strand breaks are:

- homing endonucleases
- zinc finger nucleases


An alternative approach to achieve gene insertion is based on transposons. Transposons are DNA elements that spontaneously translocate from one chromosomal location to another.


Gene therapy for primary immunodeficiencies: Looking ahead, toward gene correction. Pessach IM, Notarangelo LD. J Allergy Clin Immunol. 2011 Mar 24.
Primary immunodeficiencies (PIDD)

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