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Boundary sequences stabilize transgene expression from subtle position effects in retroviral vectors. | LitMetric

Boundary sequences stabilize transgene expression from subtle position effects in retroviral vectors.

Blood Cells Mol Dis

Medical and Molecular Genetics Center, Institut d'Investigació Biomèdica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.

Published: October 2009

AI Article Synopsis

  • Transgene expression variability from integrated retroviral vectors is a significant challenge in gene therapy, especially for hematopoietic cells.
  • The study investigates the effects of adding IFN-beta SAR and 5'HS4 beta-globin insulator sequences to enhance the stability and consistency of transgene expression in a gammaretroviral vector.
  • Results indicated that the combination of these regulatory elements improved the uniformity of EGFP expression and reduced variability, suggesting a potential strategy for creating more stable retroviral vectors in gene therapy applications.

Article Abstract

Transgene expression shut-down, attenuation and/or variability from integrated retroviral vectors pose a major obstacle to gene therapy trials involving hematopoietic cells. We have undertaken a systematic assessment of the behavior of different configurations containing IFN-beta SAR and/or 5'HS4 beta-globin insulator sequences within a gammaretroviral vector optimized for high-level expression, focusing on the long-term achievement of stable, homogeneous transgene expression in the successfully transduced cells. Introduction of these cis regulatory elements did not perturb virus production and stability. Conversely, the SAR/5'HS4 insulator combination appeared to increase the homogeneity of EGFP expression in mass cultures. Furthermore, a clonal analysis of the dispersion of EGFP expression revealed that the IFN-SAR/5'HS4 insulator dyad was particularly effective in reducing the variability of transgene expression when both sequences were placed in opposite orientations within the retroviral backbone. These results may prove useful for the design of more stable retroviral expression cassettes able to counteract chromosomal position effects.

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Source
http://dx.doi.org/10.1016/j.bcmd.2009.06.001DOI Listing

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