Pre-programmed genomic integration site (GIS)

A pre-programmed genomic integration site is a specific, predetermined location within the human T-cell genome, such as the T-cell receptor alpha constant (TRAC) locus or the AAVS1 safe harbor, utilized for the precise insertion of therapeutic genes (Eyquem et al., 2017). This approach contrasts with traditional retroviral or lentiviral transduction, which results in semi-random integration and potential oncogenic risk (Sadelain et al., 2017). By using gene-editing technologies like CRISPR-Cas9, TALENs, or ZFNs, therapeutic constructs such as Chimeric Antigen Receptors (CARs) can be placed under the control of endogenous promoters, ensuring physiological expression levels and reducing T-cell exhaustion (Papapetrou & Schambach, 2016). These sites are selected to maintain genomic stability and ensure that the integrated transgene does not disrupt essential cellular functions or trigger malignant transformation. In clinical applications, targeting these sites allows for the creation of more uniform and potent “off-the-shelf” or autologous T-cell products for treating malignancies and chronic infections (Gundry et al., 2016).

Other names

Genomic safe harborGSHTargeted integration siteLanding padTRAC locusAAVS1 locusCCR5 locusHPRT locus

Site-specific genomic integration via homology-directed repair (HDR) or non-homologous end joining (NHEJ) following targeted double-strand breaks induced by site-specific nucleases.