This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xiong, W.
Right arrow Articles by Castro, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xiong, W.
Right arrow Articles by Castro, M. G.

 Previous Article  |  Next Article 

Journal of Virology, January 2006, p. 27-37, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.27-37.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulatable Gutless Adenovirus Vectors Sustain Inducible Transgene Expression in the Brain in the Presence of an Immune Response against Adenoviruses

Weidong Xiong,1 Shyam Goverdhana,1 Sandra A. Sciascia,1 Marianela Candolfi,1 Jeffrey M. Zirger,1 Carlos Barcia,1 James F. Curtin,1 Gwendalyn D. King,1 Gabriela Jaita,1 Chunyan Liu,1 Kurt Kroeger,1 Hasmik Agadjanian,1 Lali Medina-Kauwe,1 Donna Palmer,2 Philip Ng,2 Pedro R. Lowenstein,1 and Maria G. Castro1*

Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Department of Medicine and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, 8700 Beverly Blvd., Davis Bldg., Room 5090, Los Angeles, California 90048,1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770302

Received 10 August 2005/ Accepted 7 October 2005

In view of recent serious adverse events and advances in gene therapy technologies, the use of regulatable expression systems is becoming recognized as indispensable adjuncts to successful clinical gene therapy. In the present work we optimized high-capacity adenoviral (HC-Ad) vectors encoding the novel tetracycline-dependent (TetOn)-regulatory elements for efficient and regulatable gene expression in the rat brain in vivo. We constructed two HC-Ad vectors encoding ß-galactosidase (ß-gal) driven by a TetOn system containing the rtTASsM2 transactivator and the tTSKid repressor under the control of the murine cytomegalovirus (mCMV) (HC-Ad-mTetON-ß-Gal) or the human CMV (hCMV) promoter (HC-Ad-hTetON-ß-Gal). Expression was tightly regulatable by doxycycline (Dox), reaching maximum expression in vivo at 6 days and returning to basal levels at 10 days following the addition or removal of Dox, respectively. Both vectors achieved higher transgene expression levels compared to the expression from vectors encoding the constitutive mCMV or hCMV promoter. HC-Ad-mTetON-ß-Gal yielded the highest transgene expression levels and expressed in both neurons and astrocytes. Antivector immune responses continue to limit the clinical use of vectors. We thus tested the inducibility and longevity of HC-Ad-mediated transgene expression in the brain of rats immunized against adenovirus by prior intradermal injections of RAds. Regulated transgene expression from HC-Ad-mTetON-ß-Gal remained active even in the presence of a significant systemic immune response. Therefore, these vectors display two coveted characteristics of clinically useful vectors, namely their regulation and effectiveness even in the presence of prior immunization against adenovirus.

* Corresponding author. Mailing address: Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis Building, Research Pavilion, Room 5090, Los Angeles, CA 90048. Phone: (310) 423-7303. Fax: (310) 423-7308. E-mail: castromg{at}cshs.org.

Journal of Virology, January 2006, p. 27-37, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.27-37.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Puntel, M., Barrett, R. J., Mondkar, S., Saxena, V., Kroeger, K. M., Muhammad, A. K. M., Liu, C., Bondale, N., Sciascia, S., Xiong, W., Shi, Y., Salem, A., Zadmehr, A., Huynh, P., Palmer, D., Ng, P., Castro, M. G., Lowenstein, P. R. (2009). Herpes Simplex Virus Type 1 Thymidine Kinase Sequence Fused to the lacZ Gene Increases Levels of {beta}-Galactosidase Activity per Genome of High-Capacity but Not First-Generation Adenoviral Vectors In Vitro and In Vivo. J. Virol. 83: 2004-2010 [Abstract] [Full Text]  
  • King, G. D., Muhammad, A. K. M. G., Xiong, W., Kroeger, K. M., Puntel, M., Larocque, D., Palmer, D., Ng, P., Lowenstein, P. R., Castro, M. G. (2008). High-Capacity Adenovirus Vector-Mediated Anti-Glioma Gene Therapy in the Presence of Systemic Antiadenovirus Immunity. J. Virol. 82: 4680-4684 [Abstract] [Full Text]  
  • Curtin, J. F., Candolfi, M., Xiong, W., Lowenstein, P. R., Castro, M. G. (2008). Turning the gene tap off; implications of regulating gene expression for cancer therapeutics. Molecular Cancer Therapeutics 7: 439-448 [Abstract] [Full Text]  
  • Candolfi, M., Pluhar, G. E., Kroeger, K., Puntel, M., Curtin, J., Barcia, C., Muhammad, A.K.M. G., Xiong, W., Liu, C., Mondkar, S., Kuoy, W., Kang, T., McNeil, E. A., Freese, A. B., Ohlfest, J. R., Moore, P., Palmer, D., Ng, P., Young, J. D., Lowenstein, P. R., Castro, M. G. (2007). Optimization of adenoviral vector-mediated transgene expression in the canine brain in vivo, and in canine glioma cells in vitro. Neuro Oncol Duke 9: 245-258 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»