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Tightly Regulated Long-Term Erythropoietin Expression In Vivo Using Tet-Inducible Recombinant Adeno-Associated Viral Vectors
- Source :
- Human Gene Therapy; January 2002, Vol. 13 Issue: 2 p335-342, 8p
- Publication Year :
- 2002
-
Abstract
- Recombinant adeno-associated viral (rAAV) vectors containing an improved tetracycline (tet) system of transcriptional regulation are an efficient strategy for the control of long-term therapeutic gene expression. In vivo studies with the original tet-off and tet-on vectors, while promising, have failed to demonstrate complete repression in the uninduced state. To address this issue, we incorporated the tTSkid fusion of the tet repressor and a KRAB-derived transcriptional silencer into the tet-on system in the context of rAAV vectors. The tTSkid repressor and rtTA activator were expressed constituitively from a regulator vector, and the repressor and an erythropoietin (Epo) transgene were expressed inducibly via a second vector. Following intramuscular co-injection of these vectors, we observed repeated induction of serum Epo protein following drug administration and undetectable levels after its withdrawal. Four cycles of regulation were achieved over a 32-week period. Thus, the tet-on system plus the tTSkid repressor delivered via nonpathogenic rAAV vectors is a powerful tool for controlling the in vivo expression of therapeutic transgenes. In a clinical setting, the repressor could provide a mechanism for abolishing transgene expression if it were no longer needed or if the safety of a patient became compromised.
Details
- Language :
- English
- ISSN :
- 10430342 and 15577422
- Volume :
- 13
- Issue :
- 2
- Database :
- Supplemental Index
- Journal :
- Human Gene Therapy
- Publication Type :
- Periodical
- Accession number :
- ejs6423393
- Full Text :
- https://doi.org/10.1089/10430340252769842