Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1198-1211 |
| Number of pages | 14 |
| Journal | EMBO Molecular Medicine |
| Volume | 9 |
| Issue number | 1-2 |
| Publication status | Published - 2017 |
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Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells. / Piras, F; Riba, M; Petrillo, Carolina; Lazarevic, D; Cuccovillo, I; Bartolaccini, S; Stupka, E; Gentner, B; Cittaro, D; Naldini, L; Kajaste-Rudnitski, A.
In: EMBO Molecular Medicine, Vol. 9, No. 1-2, 2017, p. 1198-1211.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells
AU - Piras, F
AU - Riba, M
AU - Petrillo, Carolina
AU - Lazarevic, D
AU - Cuccovillo, I
AU - Bartolaccini, S
AU - Stupka, E
AU - Gentner, B
AU - Cittaro, D
AU - Naldini, L
AU - Kajaste-Rudnitski, A
PY - 2017
Y1 - 2017
N2 - 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. © 2017 EMBO.
AB - 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. © 2017 EMBO.
M3 - Article
VL - 9
SP - 1198
EP - 1211
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 1-2
ER -