Development of gene therapy and cell therapy for central nervous system diseases

中枢神经系统疾病基因治疗和细胞治疗的发展

• 批准号: 11307024
• 负责人: YOSHIDA Jun
• 金额: $ 24.38万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307024/
• 关键词: CNS disease; Gene therapy; Cell therapy; Genetic analysis

We have been studying the genetic and biological analysis of central nervous system(CNS)diseases, and the development of gene therapy and cell therapy for the diseases.1. Brain tumors(1)we examined-PTEN abnormality of human glioma cell lines and confirmed the deletion in human glioma cell line A172. When we transfected PTEN gene to A172, the growth was inhibited and the extension of dendrites was also suppressed. This is based on the suppression of anchorage independent cell growth by dephosphorylation of Tyr387 on focal adhesion kinase(FAK)by PTEN.(2)It is suggested that fibroblast growth factor receptor(FGFR)-2 may be one of the prognostic factors in human glioma. (3)As basic research on the development of new gene therapies, we confirmed the following findings : (1)adenovirus-mediated transfer of p33^<INGI> with p53 drastically augments apoptosis in gliomas. (2)Adenovirus-mediated overexpression of Fas induces apoptosis of gliomas. (3)Adenovirus-mediated transfer of caspase-3 with Fas ligand induces dramatic apoptosis in gliomas. (4)Adenovirus-mediated transfer of p53 and Fas ligand dramatically enhances apoptosis in gliomas. (5)Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas. (6)Fiber-mutant E1B-defective adenovirus has highly augmented cytopathic effect against gliomas. (4)As clinical studies, we established human gene therapy vector producing facility, human gene therapy supportive laboratory, and surgical planning units in Nagoya University Hospital. In April 2000, we started the clinical trial of interferon gene therapy using cationic liposomes. From now, we are going to evaluate the safety and usefulness of the therapy.2. Cerebrovascular diseasesWe confirmed the usefulness of DNA repair enzyme, such as Apurinic/Apyrimidinic Endonuclease(APE), for cerebral infarction.

我们一直在研究中枢神经系统（CNS）疾病的遗传和生物学分析，以及基因治疗和细胞治疗的进展。脑肿瘤(1)我们检测了人胶质瘤细胞系的- pten异常，并证实在人胶质瘤细胞系A172中有缺失。转染PTEN基因后，A172的生长受到抑制，树突的延伸也受到抑制。这是基于PTEN通过去磷酸化Tyr387对局灶黏附激酶（FAK）抑制锚定非依赖性细胞生长。(2)提示成纤维细胞生长因子受体(FGFR)-2可能是影响胶质瘤预后的因素之一。(3)作为新基因疗法开发的基础研究，我们证实了以下发现：(1)腺病毒介导的p33^<INGI>与p53的转移可显著增加胶质瘤细胞凋亡。(2)腺病毒介导的Fas过表达诱导胶质瘤细胞凋亡。(3)腺病毒介导的caspase-3与Fas配体的转移可诱导胶质瘤细胞凋亡。(4)腺病毒介导的p53和Fas配体转移显著促进胶质瘤细胞凋亡。(5)腺病毒介导的caspase-8转移增加了胶质瘤细胞的死亡。(6)纤维突变型e1b缺陷腺病毒对胶质瘤具有高度增强的细胞病变作用。(4)临床研究方面，在名古屋大学附属医院建立了人类基因治疗载体生产设施、人类基因治疗支持实验室和手术计划科室。2000年4月，我们开始了使用阳离子脂质体进行干扰素基因治疗的临床试验。从现在开始，我们将评估这种疗法的安全性和有效性。脑血管疾病我们证实了DNA修复酶，如无嘌呤/无嘧啶核酸内切酶（APE）对脑梗死的有用性。

项目成果

Natsume A, Mizuno M, Ryuke Y and Yoshida J.: "Antitumor effect and cellular immunity activation by murine interferon-β gene transfer against intracerebral glioma in mouse."Gene Therapy. 6. 1626-1633 (1999)

Natsume A、Mizuno M、Ryuke Y 和 Yoshida J.：“小鼠干扰素-β 基因转移对小鼠脑内神经胶质瘤的抗肿瘤作用和细胞免疫激活。”基因治疗。6. 1626-1633 (1999)

Bouhon IA, Shinkai M, Honda H, Mizuno M, Wakabayashi T, Yoshida J, Kobayashi T.: "Synergism between mild hyperthermia and interferon-β gene expression."Cancer Letters. 139. 153-158 (1999)

Bouhon IA、Shinkai M、Honda H、Mizuno M、Wakabayashi T、Yoshida J、Kobayashi T.：“轻度热疗和干扰素-β 基因表达之间的协同作用”。《癌症快报》139. 153-158 (1999)。

Okamura T, Kurisu K, Yamamoto W, Takano H, Nishiyama M: "NADPH/quinone oxidoreductase in a priority target of glioblastoma chemotherapy."Int J Oncol. 16. 295-303 (2000)

Okamura T、Kurisu K、Yamamoto W、Takano H、Nishiyama M：“NADPH/醌氧化还原酶是胶质母细胞瘤化疗的优先目标。”Int J Oncol。

Ryuke Y, Mizuno M, Natsume A, and Yoshida J.: "Transduction Efficiency of Adenoviral Vectors Into Human Glioma Cells Increased By Association With Cationic Liposomes."Neurol Med Chir. 40. 256-260 (2000)

Ryuke Y、Mizuno M、Natsume A 和 Yoshida J.：“通过与阳离子脂质体结合，提高腺病毒载体转导人神经胶质瘤细胞的效率。”Neurol Med Chir。

Yamasaki F, Yoshioka H, Hama S, Sugiyama K, Arita K, kurusu K.: "Recurrence of meningioma Influence of vascular endothelial growth factor."Cancer. 89. 1102-1109 (2000)

Yamasaki F、Yoshioka H、Hama S、Sugiyama K、Arita K、kurusu K.：“脑膜瘤复发对血管内皮生长因子的影响。”癌症。