Integrome signatures of lentiviral gene therapy for SCID-X1 patients

Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.

Automated summary

Lentiviral vector (LV)-based gene therapy shows promise in treating various diseases. By analyzing patient samples, we found LV integrome signatures related to genomics, epigenomics, and the 3D structure of the genome. These signatures were validated in cellular therapies and differences in 3D genome signatures between LV and gamma retrovirus integromes were identified, potentially explaining the lower risk of mutations in LV-based gene therapy.