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Targeted gene therapy for brain tumor

脑肿瘤的靶向基因治疗

基本信息

批准号：
14370440
负责人：
HAMADA Hirofumi
金额：
$ 9.54万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370440/
关键词：
adenoviral vector gene therapy malignant glioma receptor cancer treatment adenoviral fiber 癌治療間葉系幹細胞 RGDモチーフ

项目摘要

The prognosis of patients with malignant glioma is extremely poor, despite the extensive surgical treatment that they receive and recent improvements in adjuvant radio-and chemotherapy. In the present study, we propose the use of gene-modified mesenchymal stem cells(MSCs) as a new tool for gene therapy of malignant brain neoplasms. Primary MSCs isolated from Fischer 344 rats possessed excellent migratory ability and exerted inhibitory effects on the proliferation of 9L glioma cells in vitro. We also confirmed the migratory capacity of MSCs in vivo and showed that when they were inoculated into the contralateral hemisphere, they migrated towards 9L glioma cells through the corpus callosum. MSCs implanted directly into the tumor localized mainly at the border between the 9L tumor cells and normal brain parenchyma, and also infiltrated into the tumor bed. Intratumoral injection of MSCs alone caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats.Due to the lack of the receptor(CAR) on MSCs, the efficiency of gene transfer into MSCs by the adenoviral vector(Adv) with the wild-type AdS fiber(Adv-F/wt) was very poor. In clear contrast, nearly 100% genetic transduction of MSCs was achieved using the integrin-targeting fiber-mutant Adv-F/RGD, which possesses a CDCRGDCFC peptide motif at the HI-loop of the fiber knob. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2(IL2) clearly augmented the antitumor effect and further prolonged the survival of tumor-bearing rats. Thus, gene therapy employing MSCs as a targeting vehicle would be promising as a new therapeutic approach for refractory, invasive brain tumors.

恶性胶质瘤患者的预后极差，尽管他们接受广泛的手术治疗和最近的辅助放射和化疗的改善。在本研究中，我们提出使用基因修饰的间充质干细胞（MSCs）作为恶性脑肿瘤基因治疗的新工具。从Fischer 344大鼠中分离的原代MSCs具有良好的迁移能力，并在体外对9 L胶质瘤细胞的增殖具有抑制作用。我们还证实了骨髓间充质干细胞在体内的迁移能力，并表明，当他们接种到对侧半球，他们通过胼胝体向9 L胶质瘤细胞迁移。直接植入肿瘤内的MSCs主要分布于9 L肿瘤细胞与正常脑实质的交界处，并向瘤床浸润。瘤内注射MSCs可显著抑制9 L肿瘤生长，提高9 L胶质瘤大鼠的存活率，但由于MSCs上缺乏CAR受体，腺病毒载体（Adv）与野生型AdS纤维（Adv-F/wt）联合转染MSCs的效率很低。与此形成鲜明对比的是，使用整合素靶向纤维突变体Adv-F/RGD实现了近100%的MSC遗传转导，该突变体在纤维节的HI环处具有CDCRGDCFC肽基序。基因修饰的骨髓间充质干细胞感染腺病毒载体编码人白细胞介素-2（IL-2）明显增强了抗肿瘤作用，并进一步延长了荷瘤大鼠的生存期。因此，采用MSC作为靶向载体的基因治疗将有望成为难治性、侵袭性脑肿瘤的新治疗方法。