Development of a new molecular therapeutic drug for brain pathology in lysosomal storage diseases

溶酶体贮积症脑病理学新型分子治疗药物的开发

基本信息

批准号：
14207106
负责人：
SUZUKI Yoshiyuki
金额：
$ 31.37万
依托单位：
International University of Health and Welfare
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

We synthesized a novel galactose derivative, N-octyl-4-epi-β-valienamine(NOEV), for a new molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G_<M1>-gangliosidosis and Morquio B disease). It has a molecular structure analogous to galactose ; molecular weight is 287.40. It is stable at room temperature, and has limited solubility in water (up to 5 mM), but freely soluble in methanol or dimethylsulfoxide. It is a potent competitive inhibitor of lysosomal (β-galactosidase in vitro. IC50 is 0.2 μM. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. We collected 50 fibroblast strains from β-galactosidase deficiency disorders from all over the world, for testing the NOEV effect in the culture system. More than 3-fold increase was observed in 35% of them. The effect was most prominent in mutations causing juvenile G_<M1>-gangliosidosis, and less effective to those causing infantile or adult G_<M1>-gangliosidosis. So far Morquio B cells did not respond significantly in this assay system. We have established a method of NOEV determination in tissues and blood, and started mouse experiments by oral administration of this compound. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

我们合成了一种新型的半乳糖衍生物，N-辛基-4-Epi-β-甲胺（NOEV），用于人类神经遗传疾病，β-半乳糖食的新分子疗法（化学链酮治疗）（g_ <m1> - g_-Gangliosidoiss和Morquio B疾病）。它具有类似于半乳糖的分子结构。分子量为287.40。它在室温下是稳定的，在水中的溶解度有限（最多5毫米），但在甲醇或二甲基硫氧化二甲醇中自由溶于溶解性。它是一种潜在的溶酶体（β-半乳糖苷酶体外的竞争抑制剂）。IC50为0.2μm。在培养基中添加NOEV在培养的人或鼠类成纤维细胞培养的人内或鼠内浓度下的培养的突变酶活性，导致细胞内的50型固定型固定型。世界各地的疾病在35％的培养系统中测试了3倍以上的疾病。通过口服这种化合物治疗的组织和血液的测定，并开始进行小鼠实验。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromosomal mapping and zygosity check of transgenes based on flanking genome sequences determined by genomic walking

DOI：
10.1538/expanim.53.103
发表时间：
2004-04-01
期刊：
EXPERIMENTAL ANIMALS
影响因子：
2.4
作者：
Noguchi, A;Takekawa, N;Suzuki, O
通讯作者：
Suzuki, O

N-octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells:: a potential chemical chaperone therapy for Gaucher disease

DOI：
10.1016/j.bbadis.2004.03.007
发表时间：
2004-08-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
影响因子：
6.2
作者：
Lin, H;Sugimoto, Y;Suzuki, Y
通讯作者：
Suzuki, Y

Design and Synthesis of Carbasugars of Biological Interest

具有生物价值的卡巴糖的设计与合成

DOI：
10.1002/chin.200504248
发表时间：
2005
期刊：
ChemInform
影响因子：
0
作者：
S. Ogawa
通讯作者：
S. Ogawa

Suzuki Y, Oshima A, Nanba E: "Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B(eds):The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Internet Version"β-Galactosidase deficiency(β-galactosidosis):G_<M1>-Gangliosidosis and Morq

Suzuki Y、Oshima A、Nanba E：“Scriver CR、Beaudet AL、Sly WS、Valle D、Childs B、Vogelstein B（编辑）：遗传性疾病的代谢和分子基础，第 8 版，互联网版本”β-半乳糖苷酶缺乏症（β-半乳糖苷沉积症）：G_<M1>-神经节苷脂沉积症和 Morq