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）疾病的遗传学和生物学分析，以及疾病的基因治疗和细胞治疗的发展。脑肿瘤（1）检测了人脑胶质瘤细胞系中的-PTEN异常，并证实了人脑胶质瘤细胞系A172中的缺失。转染PTEN基因后，A172细胞生长受到抑制，树突的延伸也受到抑制。这是基于通过PTEN对粘着斑激酶（FAK）上Tyr 387的去磷酸化来抑制锚定非依赖性细胞生长。(2)It提示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)As在开发新基因疗法的基础研究中，我们证实了以下发现：（1）腺病毒介导的p33 α<INGI>和p53的转移显著增加了胶质瘤中的凋亡。（2）腺病毒介导Fas过表达诱导胶质瘤细胞凋亡。（3）腺病毒介导的Caspase-3和Fas配体的转染诱导胶质瘤细胞凋亡。（4）腺病毒介导的p53和Fas配体的转移显著促进胶质瘤细胞的凋亡。（5）腺病毒介导的caspase-8转移增加胶质瘤细胞死亡。（6）纤维突变型E1 B缺陷型腺病毒对胶质瘤的细胞病变作用显著增强。(4)As临床研究方面，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位。2000年4月，我们开始了使用阳离子脂质体的干扰素基因治疗的临床试验。从现在开始，我们将评估该疗法的安全性和有效性。脑血管疾病我们证实了DNA修复酶，如脱嘌呤/脱嘧啶核酸内切酶（APE），在脑梗死中的作用。

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.