Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells

被引:56
作者
Piras, Francesco [1 ,2 ]
Riba, Michela [3 ]
Petrillo, Carolina [1 ,2 ]
Lazarevic, Dejan [3 ]
Cuccovillo, Ivan [1 ]
Bartolaccini, Sara [1 ]
Stupka, Elia [3 ,4 ]
Gentner, Bernhard [1 ]
Cittaro, Davide [3 ]
Naldini, Luigi [1 ,2 ]
Kajaste-Rudnitski, Anna [1 ]
机构
[1] IRCCS, San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, Milan, Italy
[2] Univ Vita Salute San Raffaele, Milan, Italy
[3] IRCCS, San Raffaele Sci Inst, Ctr Translat Genom & Bioinformat, Milan, Italy
[4] Boehringer Ingelheim GmbH & Co KG, Biberach, Germany
关键词
gene therapy; hematopoietic stem and progenitor cells; innate sensing; lentiviral vectors; p53; signaling; CYTOSOLIC DNA SENSOR; GENE-THERAPY; IN-VIVO; FUNGAL-INFECTIONS; HIV-1; INFECTION; IMMUNE-RESPONSE; ATM; TRANSPLANTATION; INTEGRATION; ACTIVATION;
D O I
10.15252/emmm.201707922
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape. LV escaped innate immune sensing that instead led to robust IFN responses upon transduction with a gamma-retroviral vector. However, reverse-transcribed LV DNA did trigger p53 signaling, activated also by non-integrating Adeno-associated vector, ultimately leading to lower cell recovery ex vivo and engraftment in vivo. These effects were more pronounced in the short-term repopulating cells while long-term HSC frequencies remained unaffected. Blocking LV-induced signaling partially rescued both apoptosis and engraftment, highlighting a novel strategy to further dampen the impact of ex vivo gene transfer on HSPC. Overall, our results shed light on viral vector sensing in HSPC and provide critical insight for the development of more stealth gene therapy strategies.
引用
收藏
页码:1198 / 1211
页数:14
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