Lentiviral vector integration profiles differ in rodent postmitotic tissues

Cynthia C. Bartholomae, Anne Arens, Kamaljit S. Balaggan, Rafael J. Yá̃ez-Mũoz, Eugenio Montini, Steven J. Howe, Anna Paruzynski, Bernhard Korn, Jens Uwe Appelt, Angus MacNeil, Daniela Cesana, Ulrich Abel, Hanno Glimm, Luigi Naldini, Robin R. Ali, Adrian J. Thrasher, Christof Von Kalle, Manfred Schmidt

Research output: Contribution to journalArticle

Abstract

Lentiviral vectors with self-inactivating (SIN) long terminal repeats (LTRs) are promising for safe and sustained transgene expression in dividing as well as quiescent cells. As genome organization and transcription substantially differs between actively dividing and postmitotic cells in vivo, we hypothesized that genomic vector integration preferences might be distinct between these biological states. We performed integration site (IS) analyses on mouse dividing cells (fibroblasts and hematopoietic progenitor cells (HPCs)) transduced ex vivo and postmitotic cells (eye and brain) transduced in vivo. As expected, integration in dividing cells occurred preferably into gene coding regions. In contrast, postmitotic cells showed a close to random frequency of integration into genes and gene spare long interspersed nuclear elements (LINE). Our studies on the potential mechanisms responsible for the detected differences of lentiviral integration suggest that the lowered expression level of Psip1 reduce the integration frequency in vivo into gene coding regions in postmitotic cells. The motif TGGAA might represent one of the factors for preferred lentiviral integration into mouse and rat Satellite DNA. These observations are highly relevant for the correct assessment of preclinical biosafety studies, indicating that lentiviral vectors are well suited for safe and effective clinical gene transfer into postmitotic tissues.

Original languageEnglish
Pages (from-to)703-710
Number of pages8
JournalMolecular Therapy
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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