Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: An implication for gene therapy targeting congenital protein deficiencies

  • Authors:
    • Shin Sasaki
    • James M. Smith
    • Keiko Takase
    • Kenji Okuda
    • Norihisa Ishii
    • Fumihiko Takeshita
  • View Affiliations

  • Published online on: August 1, 2006     https://doi.org/10.3892/ijmm.18.2.289
  • Pages: 289-297
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Maintenance of high-level transgene expression is the main challenge in current gene therapy. Although the cytomegalovirus (CMV) promoter/enhancer or its derivative the CAG promoter has been harnessed in current gene therapy vectors, transgene expression by these vectors is often transient and remains at suboptimal levels due to undefined mechanisms, possibly including the shortage of transcriptional machinery. To overcome this drawback, we designed a novel transcrip-tional control system, designated here as transcription factor-supercharging promoter system, in which transgene expression is regulated by the positive feedback circuit consisting of cis- and trans-acting elements of gene expression machinery. Among combinations of these elements, a plasmid composed of a target gene expression cassette driven by the chimeric CMV promoter containing repetitive 12-O-tetradecanoylphorbol-13-acetate-responsive elements as cis-acting elements (CMV-TTT) and expression cassettes for c-Fos and c-Jun genes as trans-acting elements facilitated high and long-term (>10 months) expression of a transgene after its intramuscular electroporation-mediated delivery in mice. Since human secretory alkaline phosphatase was used as a reporter, it was suggested that the immune evasion mechanism elicited by the CMV-TTT and/or c-Fos/ c-Jun expression also contributed to the sustained expression in mice. Our strategy may open a new avenue for a gene therapy that involves lifelong supplementation of a deficient protein that could be targeted by the host's immune system.

Related Articles

Journal Cover

August 2006
Volume 18 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Sasaki S, Smith JM, Takase K, Okuda K, Ishii N and Takeshita F: Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: An implication for gene therapy targeting congenital protein deficiencies. Int J Mol Med 18: 289-297, 2006.
APA
Sasaki, S., Smith, J.M., Takase, K., Okuda, K., Ishii, N., & Takeshita, F. (2006). Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: An implication for gene therapy targeting congenital protein deficiencies. International Journal of Molecular Medicine, 18, 289-297. https://doi.org/10.3892/ijmm.18.2.289
MLA
Sasaki, S., Smith, J. M., Takase, K., Okuda, K., Ishii, N., Takeshita, F."Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: An implication for gene therapy targeting congenital protein deficiencies". International Journal of Molecular Medicine 18.2 (2006): 289-297.
Chicago
Sasaki, S., Smith, J. M., Takase, K., Okuda, K., Ishii, N., Takeshita, F."Activator protein 1-mediated transcriptional regulation strategy sustains long-term expression of a xenogeneic gene product in vivo: An implication for gene therapy targeting congenital protein deficiencies". International Journal of Molecular Medicine 18, no. 2 (2006): 289-297. https://doi.org/10.3892/ijmm.18.2.289