학술논문
Integrome signatures of lentiviral gene therapy for SCID-X1 patients.
Document Type
article
Author
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
Source
Science Advances. 9(40)
Subject
Language
Abstract
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.