THE PHARMACOLOGIC TREATMENT OF FABRY DISEASE

法布里病的药物治疗

• 批准号: 6350732
• 负责人: JAMES ALAN SHAYMAN
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350732
• 关键词: Fabry's disease; cell line; ceramides; combinatorial chemistry; drug screening /evaluation; enzyme inhibitors; gene targeting; genetically modified animals; hexosyltransferase; laboratory mouse; metabolism disorder chemotherapy; nonhuman therapy evaluation; peptide library; Fabry's disease; cell line; ceramides; combinatorial chemistry; drug screening /evaluation; enzyme inhibitors; gene targeting; genetically modified animals; hexosyltransferase; laboratory mouse; metabolism disorder chemotherapy; nonhuman therapy evaluation; peptide library

Alpha-Galactosidase A deficiency (Fabry Disease) is an inherited X-linked disorder resulting in deficient activity of the lysosomal hydrolase, alpha-galactosidase A. In hemizygous males the phenotypic expression of this disorder is manifest by the accumulation of glycosphingolipids containing alpha-galactosyl linkages. These glycosphingolipids include galabiosylceramide and globotriosylceramide, glycolipids which serve as the receptor for shigatoxin. With the exception of galabiosylceramide, the accumulated glycolipids contain glucosylceramide as their base cerebroside. Globotriosylceramide is the primary lipid which accumulates in the tissues of affected patients. The major clinical manifestations of Fabry disease include renal failure, cerebral vascular disease, myocardial infarction, intense pain due to peripheral nervous system involvement, and skin lesions termed angiokeratomas. We propose as the primary hypothesis for these studies that the selective pharmacological inhibition of glucosylceramide synthase will prevent the complications of Fabry disease. The following specific aims are proposed to test this hypothesis. 1. To generate a combinatorial library of D-threo-PDMP congeners by diversifying the aromatic function and tertiary amine of the parent compound. To screen this library for inhibition of glucosylceramide synthase. 2. To test novel glucosylceramide synthase inhibitors for their therapeutic index by comparing the inhibitory activity against glucosylceramide synthase, galactosylceramide synthase, and ceramide transacylase. 3. To evaluate the role of candidate glucosylceramide synthase inhibitors in reversing the phenotype of primary and immortalized cells from alpha-galactosidase knockout mice and from immortalized cells from patients with Fabry disease. 4. To test candidate inhibitors in alpha-galactosidase deficient knockout mice for prevention of the Fabry phenotype.

α-半乳糖苷酶A缺乏症（Fabry病）是一种遗传性的X连锁疾病，导致溶酶体水解酶的活性不足，Alpha-galactosidase A.在半细胞雄性中，这种疾病的表型表达表现为含有含有alpha-galpha-galparcactosyl sillpactosyl链接的糖磷脂的积累。 这些糖磷脂包括甘油酰胺和球粒蛋白酶，糖脂，它们用作志毒素的受体。 除甘油酰胺类药物外，累积的糖脂含有葡萄糖基酰胺作为其碱性大脑的。 Globotriosylceramide是在受影响患者的组织中积聚的主要脂质。 法布里疾病的主要临床表现包括肾衰竭，脑血管疾病，心肌梗塞，由于周围神经系统受累而引起的剧烈疼痛以及称为血管疾病的皮肤病变。 我们认为这些研究的主要假设是，选择性药理抑制葡萄糖酰亚胺合酶将防止Fabry疾病的并发症。提出了以下特定目的来检验这一假设。 1。通过多样化母体化合物的芳族函数和三级胺来生成D-Threo-PDMP同类物的组合库。 筛选该库以抑制葡萄糖基酰胺合酶。 2。通过比较针对葡萄糖基酶合酶，半乳糖基酶合酶和神经酰胺透镜的抑制活性来测试新型葡萄糖基酶合酶抑制剂的治疗指数。 3。评估候选葡萄糖基酶合酶抑制剂在逆转α-半乳糖苷酶基因敲除小鼠的原代和永生细胞的表型中的作用，以及来自法布里病患者的永生细胞的作用。 4。测试α-半乳糖苷酶缺乏敲除小鼠的候选抑制剂，以预防Fabry表型。