Document Detail

Regulatable gutless adenovirus vectors sustain inducible transgene expression in the brain in the presence of an immune response against adenoviruses.
MedLine Citation:
PMID:  16352528     Owner:  NLM     Status:  MEDLINE    
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 beta-galactosidase (beta-gal) driven by a TetOn system containing the rtTAS(s)M2 transactivator and the tTS(Kid) repressor under the control of the murine cytomegalovirus (mCMV) (HC-Ad-mTetON-beta-Gal) or the human CMV (hCMV) promoter (HC-Ad-hTetON-beta-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-beta-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-beta-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.
Weidong Xiong; Shyam Goverdhana; Sandra A Sciascia; Marianela Candolfi; Jeffrey M Zirger; Carlos Barcia; James F Curtin; Gwendalyn D King; Gabriela Jaita; Chunyan Liu; Kurt Kroeger; Hasmik Agadjanian; Lali Medina-Kauwe; Donna Palmer; Philip Ng; Pedro R Lowenstein; Maria G Castro
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of virology     Volume:  80     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2005-12-14     Completed Date:  2007-01-26     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  27-37     Citation Subset:  IM    
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis Building, Research Pavilion, Room 5090, Los Angeles, CA 90048, USA.
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MeSH Terms
Adenoviruses, Human / genetics,  physiology*
Antigens, Viral / genetics,  metabolism*
Gene Expression Regulation
Genetic Vectors*
Tetracycline / pharmacology*
Transgenes / drug effects,  physiology*
beta-Galactosidase / biosynthesis,  genetics
Grant Support
1 R03 TW006273-01/TW/FIC NIH HHS; 1 RO1 NS42893/NS/NINDS NIH HHS; 1RO1 NS44556.01/NS/NINDS NIH HHS; R21 NS47298/NS/NINDS NIH HHS; U54 4 NS04-5309/NS/NINDS NIH HHS
Reg. No./Substance:
0/Antigens, Viral; 60-54-8/Tetracycline; EC

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