Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection

Blood. 2011 May 19;117(20):5332-9. doi: 10.1182/blood-2010-09-306761. Epub 2011 Mar 14.

Abstract

A recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed high-throughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from γ-retroviral vector-based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenoleukodystrophy / genetics
  • Adrenoleukodystrophy / therapy
  • Animals
  • Clinical Trials as Topic
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Genetic Vectors*
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Lentivirus / genetics*
  • Mice
  • Mice, Knockout
  • Transplantation Chimera / genetics
  • Virus Integration / genetics

Substances

  • DNA-Binding Proteins
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Rag2 protein, mouse