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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

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 rtTAS^sM2 transactivator and the tTS^Kid 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.

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