Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell

Luca Biasco, Alessandro Ambrosi, Danilo Pellin, Cynthia Bartholomae, Immacolata Brigida, Maria Grazia Roncarolo, Clelia Di Serio, Christof Von Kalle, Manfred Schmidt, Alessandro Aiuti

Research output: Contribution to journalArticlepeer-review

Abstract

The analysis of genomic distribution of retroviral vectors is a powerful tool to monitor 'vector-on-host' effects in gene therapy (GT) trials but also provides crucial information about 'host-on-vector' influences based on the target cell genetic and epigenetic state. We had the unique occasion to compare the insertional profile of the same therapeutic moloney murine leukemia virus (MLV) vector in the context of the adenosine deaminase-severe combined immunodeficiency (ADA-SCID) genetic background in two GT trials based on infusions of transduced mature lymphocytes (peripheral blood lymphocytes, PBL) or a single infusion of haematopoietic stem/progenitor cells (HSC). We found that vector insertions are cell-specific according to the differential expression profile of target cells, favouring, in PBL-GT, genes involved in immune system and T-cell functions/pathways as well as T-cell DNase hypersensitive sites, differently from HSC-GT. Chromatin conformations and histone modifications influenced integration preferences but we discovered that only H3K27me3 was cell-specifically disfavoured, thus representing a key epigenetic determinant of cell-type dependent insertion distribution. Our study shows that MLV vector insertional profile is cell-specific according to the genetic/chromatin state of the target cell both in vitro and in vivo in patients several years after GT. See accompanying Closeup by Baum DOI: http://dx.doi.org/10.1002/emmm.201000110.

Original languageEnglish
Pages (from-to)89-101
Number of pages13
JournalEMBO Molecular Medicine
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 2011

Keywords

  • Chromatin modifications
  • Gene therapy
  • Haematopoietic stem cells
  • Lymphocytes
  • Retroviral integrations

ASJC Scopus subject areas

  • Molecular Medicine

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