Details

Autor(en) / Beteiligte

• RENDAHL, Katherine G
• QUIROZ, Dulce
• LADNER, Martha
• COYNE, Mazie
• SELTZER, Jon
• MANNING, William C
• ESCOBEDO, Jaime A

Titel

Tightly regulated long-term erythropoietin expression in vivo using tet-inducible recombinant adeno-associated viral vectors

Ist Teil von

• Human gene therapy, 2002-01, Vol.13 (2), p.335-342

Ort / Verlag

Larchmont, NY: Liebert

Erscheinungsjahr

2002

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 tTS(kid) fusion of the tet repressor and a KRAB-derived transcriptional silencer into the tet-on system in the context of rAAV vectors. The tTS(kid) 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 tTS(kid) 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.