Science advances · 2023
Integrome signatures of lentiviral gene therapy for SCID-X1 patients.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yan Koon-Kiu, Condori Jose, Ma Zhijun, Metais Jean-Yves, Ju Bensheng, Ding Liang, Dhungana Yogesh, Palmer Lance E, Langfitt Deanna M, Ferrara Francesca, Throm Robert, Shi Hao, Risch Isabel, Bhatara Sheetal, Shaner Bridget, Lockey Timothy D, Talleur Aimee C, Easton John, Meagher Michael M, Puck Jennifer M, Cowan Morton J, Zhou Sheng, Mamcarz Ewelina, Gottschalk Stephen, Yu Jiyang
Аннотация
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.