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。在半合子雄性中，这种疾病的表型表达表现为含有α -半乳糖苷键的鞘糖脂的积累。这些鞘糖脂包括半肽神经酰胺和球三肽神经酰胺，它们是作为志贺毒素受体的糖脂。除了半乳糖神经酰胺外，积累的糖脂含有葡萄糖神经酰胺作为其基础脑苷。globotriosylneuroide是主要的脂质，在患者的组织中积累。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以及称为血管角化瘤的皮肤病变。我们提出作为这些研究的主要假设，选择性药理抑制糖基神经酰胺合成酶将预防法布里病的并发症。提出以下具体目标来检验这一假设。1. 通过分散母体化合物的芳族功能和叔胺，生成d - 3 - pdmp同系物组合文库。筛选该文库对葡萄糖神经酰胺合成酶的抑制作用。2. 通过对葡萄糖神经酰胺合成酶、半乳糖神经酰胺合成酶和神经酰胺转酰基酶的抑制活性比较，考察新型葡萄糖神经酰胺合成酶抑制剂的治疗指标。3. 评估候选葡萄糖神经酰胺合成酶抑制剂在逆转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测试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.