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

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，以及针对这些疾病的基因治疗和细胞治疗的发展。脑肿瘤(1)我们检测了人脑胶质瘤细胞系中-PTEN的异常，证实了人脑胶质瘤细胞系A172中-PTEN基因的缺失。将PTEN基因导入A172细胞后，细胞生长受到抑制，树突状突起伸展也受到抑制。这是基于PTEN通过使粘着斑激酶(FAK)Tyr387去磷酸化而抑制非锚定依赖性细胞生长。(2)成纤维细胞生长因子受体(FGFR)-2可能是人脑胶质瘤的预后因素之一。(3)作为开发新的基因治疗方法的基础研究，我们证实了以下发现：(1)腺病毒介导的p33^-lt；Ingi&gt；P53基因转移显著增加了胶质瘤细胞的凋亡。(2)腺病毒介导的Fas过表达可诱导胶质瘤细胞凋亡。(3)腺病毒介导的带有Fas配体的caspase-3基因转移可诱导胶质瘤细胞发生明显的细胞凋亡。(4)腺病毒介导的p53和Fas配体转移显著促进了胶质瘤细胞的凋亡。(5)腺病毒介导的caspase-8基因转移增强了胶质瘤细胞的死亡。(6)纤维突变型E1B缺陷型腺病毒对脑胶质瘤具有高度的细胞病变效应。(4)作为临床研究，我们在名古屋大学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单元。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。从现在起，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，如阿嘌呤/脱嘧啶核酸内切酶(APE)在脑梗塞中的有效性。

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.