Gene Therapy for Genetic Neurodegenerative Disorders by Cultured Microglia Cell for Gene Delivery

通过培养小胶质细胞进行基因传递治疗遗传性神经退行性疾病

• 批准号: 11694306
• 负责人: TANAKA Akemi
• 金额: $ 7.23万
• 依托单位: Osaka City University Graduate School of Medicine
• 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-11694306/
• 关键词: MICROGLIA CELL; ADENOVIRUS VECTOR; LYSOSOMAL STORAGE DISEASE; β-GLUCURONIDASE DEFICIENCY; GENE EXPRESSION; GFP

Gene delivery into the brain via blood vessels is quite difficult because of the blood-brain-barrier (BBB). It is speculated that microglia cells would go through BBB.We established a strain of cultured microglia cell from newborn mice brain for the vehicle of gene into the brain. The cells were labeled with a reporter gene of GFP and injected into the left ventricle of heart of Sly mice. Sly mouse, the deficiency of β-glucuronidase, is a mouse model for human disease of mucopolys accharidosis type VII, which is a systemic disorder including the brain caused by the accumulation of glycosaminoglycans. It is suggested that delivery of the deficient enzyme or the gene into each organ would improve the disease.In the literature, a number of experiments of gene therapy for the brain have been done, but none of them has not been successful. In our study, the cultured microglia cells could enter the brain tissue via blood vessel only when BBB was injured by the disease progression, but they do not go through normal BBB.

由于血脑屏障（BBB）的存在，通过血管将基因递送到脑中是相当困难的。我们建立了一株体外培养的新生小鼠脑小胶质细胞，作为基因进入脑的载体。将细胞用GFP报告基因标记并注射到Sly小鼠的左心室中。β-葡萄糖醛酸苷酶缺乏的Sly小鼠是人类粘多糖病VII型的小鼠模型，粘多糖病VII型是一种由糖胺聚糖蓄积引起的包括大脑在内的全身性疾病。在文献中，已经进行了许多脑基因治疗的实验，但没有一个是不成功的。本研究中，培养的小胶质细胞只有在疾病进展导致血脑屏障损伤时才能通过血管进入脑组织，而不通过正常血脑屏障。

项目成果

Nagano T, Nakamura A, Konno D, Kurata M, Yagi H, Sato M: "A2-Pancortins (Pancortin-3 and -4) are the dominant Pancortins during neocortical development."J.Neurochem.. 75. 1-8 (2000)

Nagano T、Nakamura A、Konno D、Kurata M、Yagi H、Sato M：“A2-Panchortin（Pancortin-3 和 -4）是新皮质发育过程中的主要 Pancortin。”J.Neurochem.. 75. 1-8 (

Oya Y,Proia RL et al.: "Distribution of enzyme-bearing cells in GM2 gangliosidosis nice : regionally specific pattern of cellular infiltration following bone marrow transplantation."Acta Neuropathol.. 99. 161-168 (2000)

Oya Y、Proia RL 等人：“GM2 神经节苷脂沉积症中含酶细胞的分布很好：骨髓移植后细胞浸润的区域特异性模式。”Acta Neuropathol.. 99. 161-168 (2000)

Keng VW, Yagi H, Ikawa M, Nagano T, Myint Z, Yamada K, Tanaka T, Sato A, Muramatsu I, Okabe M, Sato M, Noguchi T: "Homeobox gene Hex is essential for onset of mouse embrionicliver development."Biochem.Biophys.Res.Commun.. 1276. 1155-1161 (2000)

Keng VW、Yagi H、Ikawa M、Nagano T、Myint Z、Yamada K、Tanaka T、Sato A、Muramatsu I、Okabe M、Sato M、Noguchi T：“同源框基因 Hex 对于小鼠胚胎肝发育的开始至关重要。”

Kimura M, Tanabe K, Krishna S, Tsuboi T, Saito-Ito A, Otani S, Ogura H: "Gametocyte-dominant expression of a novel P-type ATPase in Plasmodium yoelii."Mol.Biochem.Parasitol.. 104. 331-336 (1999)

Kimura M、Tanabe K、Krishna S、Tsuboi T、Saito-Ito A、Otani S、Ogura H：“约氏疟原虫中一种新型 P 型 ATP 酶的配子细胞显性表达。”Mol.Biochem.Parasitol.. 104. 331

Saitoh S,Oiso N et al.: "Oculocutaneous albinizm type 2 with a P gene missence mutation in a patient with Angelman syndrome"J.Ned.genet.. 37・5. 392-394 (2000)

Saitoh S、Oiso N 等：“Angelman 综合征患者中伴有 P 基因错失突变的 2 型眼皮肤白化病”J.Ned.genet.. 37・5 (2000)。