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Retrovirus silencing and vector design: relevance to normal and cancer stem cells?

James Ellis1, Shuyuan Yao

  • 1Developmental Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada. jellis@sickkids.ca

Current Gene Therapy
|August 17, 2005
PubMed

Insights

Gene therapy in stem cells faces challenges due to vector silencing. Epigenetic pathways like DNA methylation and histone modifications silence oncoretrovirus and lentivirus vectors, impacting gene expression during differentiation.

Area of Science:

  • Biotechnology
  • Molecular Biology
  • Gene Therapy

Background:

  • Transcriptional silencing of vectors is a major hurdle for effective gene therapy in stem cells.
  • Oncoretrovirus and lentivirus vectors are susceptible to epigenetic silencing mechanisms.
  • Vector expression can be variegated in stem cells and lost during differentiation.

Purpose of the Study:

  • To discuss recent data on epigenetic silencing of viral vectors in stem cells.
  • To propose a novel model for retrovirus silencing.
  • To provide recommendations for optimizing retrovirus vector design for stem cell gene therapy.

Main Methods:

  • Review of recent data on epigenetic silencing pathways.
  • Development of a novel model for retrovirus silencing.
  • Analysis of chromatin modifications and their role in silencing.

Main Results:

  • Oncoretrovirus and lentivirus vectors are silenced by epigenetic pathways, including DNA methylation and histone modifications.
  • These vectors can exhibit variegated expression in stem cells, often lost during differentiation.
  • A model is proposed where epigenetic factors compete to silence proviruses.

Conclusions:

  • Optimized retrovirus vector designs should exclude silencer elements, include regulatory elements and insulators, and avoid non-mammalian reporters.
  • Cancer stem cells may share silencing pathways with normal stem cells.
  • Improved vector designs hold promise for gene therapy in both normal and cancer stem cells.

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