期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：15
页码：8657-8662
DOI：10.1073/pnas.96.15.8657
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Effective delivery of secreted proteins by gene therapy will require a vector that directs stable delivery of a transgene and a regulatory system that permits pharmacologic control over the level and kinetics of therapeutic protein expression. We previously described a regulatory system that enables transcription of a target gene to be controlled by rapamycin, an orally bioavailable drug. Here we demonstrate in vivo regulation of gene expression after intramuscular injection of two separate adenovirus or adeno-associated virus (AAV) vectors, one encoding an inducible human growth hormone (hGH) target gene, and the other a bipartite rapamycin-regulated transcription factor. Upon delivery of either vector system into immunodeficient mice, basal plasma hGH expression was undetectable and was induced to high levels after administration of rapamycin. The precise level and duration of hGH expression could be controlled by the rapamycin dosing regimen. Equivalent profiles of induction were observed after repeated administration of single doses of rapamycin over many months. AAV conferred stable expression of regulated hGH in both immunocompetent and immunodeficient mice, whereas adenovirus-directed hGH expression quickly extinguished in immunocompetent animals. These studies demonstrate that the rapamycin-based regulatory system, delivered intramuscularly by AAV, fulfills many of the conditions necessary for the safe and effective delivery of therapeutic proteins by gene therapy.
