THE PHARMACOLOGIC TREATMENT OF FABRY DISEASE

α-半乳糖苷酶A缺乏症（法布里病）是一种遗传性X连锁疾病，导致溶酶体水解酶α-半乳糖苷酶A活性不足。 在半合子男性中，这种疾病的表型表达表现为含有α-半乳糖基键的鞘糖脂的积累。 这些鞘糖脂包括半乳糖神经酰胺和globotriosylceramide，作为志贺毒素受体的糖脂。 除半乳糖神经酰胺外，积累的糖脂含有葡萄糖神经酰胺作为其基础糖苷。 Globotriosylceramide是在受影响患者的组织中积累的主要脂质。 法布里病的主要临床表现包括肾功能衰竭、脑血管疾病、心肌梗死、周围神经系统受累引起的剧烈疼痛和称为血管角化瘤的皮肤病变。 我们提出这些研究的主要假设是，选择性药理学抑制葡萄糖神经酰胺合酶将预防法布里病的并发症。为检验这一假设，提出了以下具体目标。1.通过使母体化合物的芳族官能团和叔胺多样化来产生D-苏型-Pestrin同源物的组合文库。 筛选该文库的葡糖神经酰胺合酶抑制作用。 2.通过比较对葡糖神经酰胺合酶、半乳糖神经酰胺合酶和神经酰胺转酰酶的抑制活性，测试新型葡糖神经酰胺合酶抑制剂的治疗指数。 3.评价候选葡糖神经酰胺合酶抑制剂在逆转α-半乳糖苷酶敲除小鼠和法布里病患者永生化细胞的原代和永生化细胞表型中的作用。 4.在α-半乳糖苷酶缺陷敲除小鼠中检测候选抑制剂，以预防法布里表型。

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.