A study of the new therapeutic method and the clinical application for central nervous involvement in inherited metabolic diseases.

遗传性代谢病中枢神经受累的新治疗方法及临床应用研究。

• 批准号: 13557070
• 负责人: NANBA Eiji
• 金额: $ 8.19万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557070/
• 关键词: chemical chaperon; treatment; lysosomal storage disease; 低分子物質; 先天代謝異常; GM1-ガングリオシドーシス; 中枢神経障害; 先天代謝異常症; G_<M1>-ガングリオドシドーシス

The chemical chaperon therapy for inherited metabolic diseases including GM1-gangliosidois have been developed in the study. GM1-gangliosidosis which caused by deficiency of β-galactosidase in lysosome, is manifested by central nervous involvement. A new therapeutic method have been developed in the study. Initially more than 27 types of murine model cells containing human β-galactosidase mutation have been created. A galactose derivative, N-octyl-4-epi-β-valienamine (NOEV), which is a potent inhibitor of lysosomal β-galactosidase in vitro, was synthesized. Addition of NOEV in the culture medium restored mutant enzyme activity in murine model cells, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1gangliosidosis resulted in significant enhancement of the enzyme activity in the brain and other tissues. Chemical chaperon therapy may be useful for certain patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

本研究开发了包括GM 1-神经节苷脂酶在内的遗传代谢性疾病的化学分子伴侣治疗。神经节苷脂沉积症（GM 1-gangliosidosis，GM 1-gangliosidosis）是由溶酶体内β-半乳糖苷酶缺乏引起的一种以中枢神经系统受累为主要表现的疾病。在这项研究中开发了一种新的治疗方法。最初，已经建立了超过27种含有人β-半乳糖苷酶突变的小鼠模型细胞。合成了一种半乳糖衍生物N-辛基-4-表-β-维列胺（NOEV），它在体外是一种有效的溶酶体β-半乳糖苷酶抑制剂。在培养基中添加NOEV恢复了鼠模型细胞中的突变酶活性，导致细胞内底物储存显著减少。对幼年GM 1神经节苷脂沉积症模型小鼠短期口服NOEV导致脑和其他组织中的酶活性显著增强。化学伴侣疗法可能对某些患有GM 1-神经节苷脂沉积症和其他可能累及中枢神经系统的溶酶体贮积病的患者有用。

项目成果

Yamamoto T, Feng JH, Higaki K, Taniguchi M, Nanba E, Ninomiya H, Ohno K.: "Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients."Brain Dev.. 26(4). 245-250 (2004)

Yamamoto T、Feng JH、Higaki K、Taniguchi M、Nanba E、Ninomiya H、Ohno K.：“尼曼匹克病 C 型患者皮肤成纤维细胞中 NPC1 mRNA 增加。”Brain Dev.. 26(4)。

Tominaga L, Ogawa Y, Taniguchi M, Ohno K, Matsuda J, Oshima A, Suzuki Y, Nanba E.: "Galactonojirimycin derivatives restore mutant human beta-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse."Brain Dev.. 23(5). 284-287

Tominaga L、Okawa Y、Taniguchi M、Ohno K、Matsuda J、Oshima A、Suzuki Y、Nanba E.：“半乳糖野尻霉素衍生物可恢复酶缺陷基因敲除小鼠成纤维细胞中表达的突变型人 β-半乳糖苷酶活性。”Brain Dev..

Saito Y, Geyer A, Sasaki R, Kuzuhara S, Nanba E, Miyasaka T, Suzuki K, Murayama S.: "Early-onset, rapidly progressive familial tauopathy with R406W mutation."Neurology. 58(5). 811-813 (2002)

Saito Y、Geyer A、Sasaki R、Kuzuhara S、Nanba E、Miyasaka T、Suzuki K、Murayama S.：“具有 R406W 突变的早发、快速进展的家族性 tau 病。”神经病学。

Yamamoto T, Pipo JR, Feng JH, Takeda H, Nanba E, Ninomiya H, Ohno K.: "Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex"Brain Dev.. 24(4). 227-230 (2002)

Yamamoto T、Pipo JR、Feng JH、Takeda H、Nanba E、Ninomiya H、Ohno K.：“日本结节性硬化症患者中的新 TSC1 和 TSC2 突变”Brain Dev.. 24(4)。

Takaura N et al.: "Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer"Gene Ther.. 10(17). 1487-1493 (2003)

Takaura N 等人：“通过新生儿静脉内基因转移减少 GM1 神经节苷脂沉积症小鼠大脑中神经节苷脂 GM1 积累”Gene Ther.. 10(17)。