Characterization of physiologically regulated vectors for the treatment of ischemic disease
Characterization of physiologically regulated vectors for the treatment of ischemic disease
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DOI：
10.1089/10430349950017185
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发表时间：
1999-09-01
影响因子：
4.2
通讯作者：
Naylor, S
中科院分区：
文献类型：
--
作者：
Boast, K;Binley, K;Naylor, S
高的治疗指数对于基于基因的治疗和化疗或放射治疗一样重要。一种方法是通过使用组织特异性调控元件进行转录靶向。一种更通用的方法是使用一种通过一系列疾病共同的参数来控制的调控因素。缺血是一系列病理的特征，从血管闭塞到癌症，低氧状态，缺氧，触发转录信号通路，该通路由与特定增强子结合的转录因子介导，即缺氧反应元件(HRE)。因此，这些观察结果导致使用HREs来驱动从肿瘤到心肌的许多靶组织中的基因表达。为了将这些观察结果转化为临床有用的载体系统，我们现在评估了一些自然衍生的HRE的效力：在各种配置下，结合最少的启动子。优化的HRE已被引入到单个转录单位逆转录病毒载体中，该载体可以携带受调控的基因表达来响应缺氧。这个新的生理调控载体的一个重要特征是低基础表达和高水平激活表达的结合，这与巨细胞病毒立即早期(CMV IE)启动子获得的表达相当，也评估了在缺氧情况下稳定mRNA的元件的作用。这些受低氧调控的载体可能有助于限制治疗性蛋白向肿瘤和缺血部位的输送。
A high therapeutic index is as important for gene-based therapies as it is for chemotherapy or radiotherapy. One approach has been transcriptional targeting through the use of tissue-specific regulatory elements. A more versatile approach would be to use a regulatory element that is controlled via a parameter common to a broad range of diseases. Ischemia is characteristic of a number of pathologies that range from vascular occlusion through to cancer, The state of low oxygen, hypoxia, triggers a transcriptional signaling pathway that is mediated by transcription factors binding to a specific enhancer, the hypoxia response element (HRE). These observations have therefore led to the use of HREs to drive gene expression in a number of target tissues from tumors to cardiac muscle. To translate these observations into a clinically useful vector system we have now assessed the potency of a number of naturally derived HREs: in various configurations combined with minimal promoters. The optimal HRE has been introduced into a single transcription unit retroviral vector that can deliver regulated gene expression in response to hypoxia. An important feature of this new physiologically regulated vector is the combination of low basal expression and high-level activated expression that is on a par with that obtained with the cytomegalovirus immediate-early (CMV IE) promoter, The role of elements that stabilize mRNA in the presence of hypoxia has also been assessed. These hypoxia-regulated vectors may have utility for restricting the delivery of therapeutic proteins to tumors and ischemic sites.