An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer
An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer
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DOI：
10.1038/sj.gt.3301001
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发表时间：
1999-10-01
期刊：
影响因子：
5.1
通讯作者：
Naylor, S
中科院分区：
文献类型：
--
作者：
Binley, K;Iqball, S;Naylor, S
重组腺病毒载体对于基因治疗具有许多优点，包括转导一系列分裂和非分裂细胞类型。然而，如果非靶细胞被转导并且受到转移基因表达的不利影响，则该宽范围可能是不利的。在这里，我们描述了一种新的腺病毒载体，其中转基因的转录被限制在低氧张力（缺氧）的病理生理条件。低氧激活许多基因的表达，主要是通过稳定与共有DNA序列（低氧反应元件; HRE）结合的bHLH/PAS转录因子家族成员。我们已经将优化的HRE表达盒配置到腺病毒载体AdOBHRE中。当用AdOBHRE转导时，包括原代人骨骼肌在内的一系列细胞类型显示低基础水平的转基因表达，其在缺氧中被高度诱导至与从CMV启动子获得的水平相当的水平。AdOBHRE载体可用于转录靶向基因治疗，用于治疗组织缺氧是主要特征的疾病，如癌症、外周动脉疾病、关节炎和贫血。
Recombinant adenoviral vectors have a number of advantages for gene therapy, including transduction of a range of dividing and non-dividing cell types. However, this broad range may be a disadvantage if non-target cells are transduced and are adversely affected by expression of the transferred gene. Here we describe a novel adenoviral vector in which transcription of the transgene is restricted to the patho-physiological condition of low oxygen tension (hypoxia). Hypoxia activates the expression of a number of genes, principally via the stabilisation of members of the bHLH/PAS family of transcription factors that bind to a consensus DNA sequence, the hypoxia response element; (HRE). We have configured an optimised HRE expression a cassette into an adenoviral vector, AdOBHRE. A range of, cell types including primary human skeletal muscle, when transduced with AdOBHRE display a low basal level oft transgene expression that is highly induced in hypoxia to; levels equivalent to that obtained from the CMV promoter. The AdOBHRE vector could be exploited for transcriptionally targeted gene therapy for the treatment of diseases such as cancer, peripheral arterial disease, arthritis and anaemia where tissue hypoxia is a cardinal feature.