Fitzsimons H L, Mckenzie J M, During M J
Division of Molecular Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Gene Ther. 2001 Nov;8(22):1675-81. doi: 10.1038/sj.gt.3301582.
Recombinant AAV is increasingly becoming the vector of choice for many gene therapy applications in the CNS, due to its lack of toxicity and high level of sustained expression. With recent improvements in the generation of pure, high titer vector stocks, the regulation of gene expression is now a key issue for successful translation of gene therapy-based treatments to the clinic. The level of the transgene protein may need to be maintained within a narrow therapeutic window for the successful treatment of human disease. The doxycycline responsive system directs a dose-responsive, tightly regulated level of gene expression and has been used successfully in transgenic mouse models. Here, we have optimized an autoregulatory, bidirectional doxycyline responsive cassette specifically for use in rAAV. We minimized the size of the cassette and decreased the basal leakiness of the system, leading to tight regulation in the rat
重组腺相关病毒（AAV）由于其无毒性和高水平的持续表达，越来越成为中枢神经系统中许多基因治疗应用的首选载体。随着近期在产生纯的、高滴度载体储备方面的改进，基因表达的调控现在是基于基因治疗的疗法成功转化到临床的关键问题。为成功治疗人类疾病，转基因蛋白水平可能需要维持在狭窄的治疗窗口内。强力霉素反应系统可实现剂量反应性、严格调控的基因表达水平，并已在转基因小鼠模型中成功应用。在此，我们专门针对重组腺相关病毒（rAAV）优化了一种自调控、双向强力霉素反应盒。我们将该反应盒的大小最小化，并降低了系统的基础渗漏，从而在大鼠中实现了严格调控
