Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors
Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors
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DOI：
10.1038/gt.2012.39
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发表时间：
2013-03-01
期刊：
影响因子：
5.1
通讯作者：
Colin, M.
中科院分区：
文献类型：
--
作者：
Lecolle, K.;Begard, S.;Colin, M.
胶质母细胞瘤是发生在成人和儿童中最具侵袭性的脑肿瘤。目前可用的化疗使患者的中位生存时间仅延长4个月。目前治疗的低效率部分是由于血脑屏障，它限制了大多数药物渗透到中枢神经系统。因此，局部区域治疗策略成为强制性的。在此背景下，病毒工具对于将基因选择性递送到肿瘤细胞中具有极大的意义。神经胶质瘤表达高水平的2型生长抑素受体（sstr 2A），精确定位为合适的目标，以提高这些肿瘤的转导效率。我们设计了一种新的腺病毒载体的基础上引入全长生长抑素（SRIF（生长激素释放抑制因子））序列到HAdV纤维蛋白的HI环。我们证明了（i）HAdV-5-SRIF摄取到细胞中是由sstr 2A介导的，（H）我们的载体在表达内源性sstr 2A的细胞中驱动高水平的基因表达，具有高达65倍的增强，以及（iii）低剂量的HAdV-5-SRIF足以感染高级别的人原代胶质母细胞瘤细胞。因此，靶向SRIF受体的腺病毒载体可能代表了一种有前途的脑肿瘤治疗方法。Gene Therapy（2013）20，283-297; doi：10.1038/gt.2012.39; 2012年5月17日在线发表
Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (H) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors. Gene Therapy (2013) 20, 283-297; doi:10.1038/gt.2012.39; published online 17 May 2012