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

Abstract:

: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.

journal_name

EMBO Mol Med

journal_title

EMBO molecular medicine

authors

Piras F,Riba M,Petrillo C,Lazarevic D,Cuccovillo I,Bartolaccini S,Stupka E,Gentner B,Cittaro D,Naldini L,Kajaste-Rudnitski A

doi

10.15252/emmm.201707922

subject

Has Abstract

pub_date

2017-09-01 00:00:00

pages

1198-1211

issue

9

eissn

1757-4676

issn

1757-4684

pii

emmm.201707922

journal_volume

9

pub_type

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