Generation of an adenovirus vector for gene therapy of pituitary tumor

迄今为止，腺病毒载体（Ads）已广泛应用于各种癌症基因治疗。这种效用主要来源于这些药物的无与伦比的能力，以完成有效的基因传递到肿瘤目标。不幸的是，在癌症的人类临床基因治疗试验中，这些优势的转化更加困难。需要克服的关键问题是目前可用的基因转移系统效率低和缺乏选择性。因此，将Ad应用于癌症基因治疗将理想地体现这两个要求——完成腺病毒受体（CAR）非依赖性基因递送的能力，作为提高载体对肿瘤靶点效率的手段；避免肝隔离的能力，作为限制潜在载体相关毒性的手段。在此，我们在体外比较了基于Ad血清型5 （Ad5）衣壳的长轴Ad载体与生长抑素配体（SS-14）在纤维环（Ad5longSS-14VEGF）中的基因转移效率。Ad5longSS-14VEGF显著降低car阳性细胞（正常器官模型）的感染性。另一方面，与Ad5相比，Ad5longSS-14VEGF显著提高了SS-14受体阳性细胞（垂体瘤模型）的感染性。我们认为，人工纤维轴延伸的Ad载体与纤维结节hi环中的生长抑素配体结合可能有助于垂体肿瘤的基因治疗。

Adenovirus vectors (Ads) have been employed for a wide variety of cancer gene therapy applications to date. This utility has derived principally from the unparalleled ability of these agents to accomplish efficient gene delivery to tumor targets. Unfortunately, translation of these advantages has been more difficult to accomplish in human clinical gene therapy trials for cancer. Critical problems to overcome are low efficiency and lack of selectivity of currently available gene transfer systems. Adaptation of Ad for cancer gene therapy applications would thus ideally embody these two mandates-the ability to accomplish adenovirus receptor (CAR)-independent gene delivery as a means to improve vector efficiency for tumor targets and the ability to avoid liver sequestration as a means to limit potential vector related toxicity. Herein, we compared gene transfer efficiencies of Ad serotype 5 (Ad5) capsid-based 'longer-shafted' Ad vector with a somatostatin ligand (SS-14) in the HI-loop of the fiber knob (Ad5longSS-14VEGF) to wild-type Ad vector in vitro. Ad5longSS-14VEGF significantly reduced infectivity in CAR-positive cells (normal organ model). On the other hand, Ad5longSS-14VEGF significantly increased infectivity in SS-14 receptor-positive cells (pituitary tumor model) compared with Ad5. We suggest that Ad vectors with artificial fiber shaft extension in combination with a somatostatin ligand in the HI-loop of the fiber knob may be useful for gene therapy of pituitary tumor.