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Integrome signatures of lentiviral gene therapy for SCID-X1 patients.
- Yan, Koon-Kiu;
- Condori, Jose;
- Ma, Zhijun;
- Metais, Jean-Yves;
- Ju, Bensheng;
- Ding, Liang;
- Dhungana, Yogesh;
- Palmer, Lance;
- Langfitt, Deanna;
- Ferrara, Francesca;
- Throm, Robert;
- Shi, Hao;
- Risch, Isabel;
- Bhatara, Sheetal;
- Shaner, Bridget;
- Lockey, Timothy;
- Talleur, Aimee;
- Easton, John;
- Meagher, Michael;
- Puck, Jennifer;
- Zhou, Sheng;
- Mamcarz, Ewelina;
- Gottschalk, Stephen;
- Yu, Jiyang;
- Cowan, Morton
- et al.
Published Web Location
https://doi.org/10.1126/sciadv.adg9959Abstract
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.
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