Metabolic Regulation and Gene Therapy for Neurogenetic Diseases

神经遗传疾病的代谢调节和基因治疗

• 批准号: 6228075
• 负责人: Roscoe O Brady
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6228075
• 关键词: Fabry's disease; Gaucher's disease; Retroviridae; alpha galactosidase; analog; bone marrow; bone marrow transplantation; ceramides; cerebrosides; clinical research; complementary DNA; disease /disorder model; gene therapy; hematopoietic stem cells; human subject; inhibitor /antagonist; laboratory mouse; mesenchyme; model design /development; neurogenetics; nonhuman therapy evaluation

In a collaborative study with investigators at the University of Oxford, UK, we are examining the effects of small molecular weight inhibitors of the formation of globotriaosylceramide in the murine analogue of Fabry disease created by scientists in DMNB and NIDCR. If these molecules prove effective in this model, their clinical effects will be evaluated in patients with Fabry disease. Since these molecules can cross the blood-brain barrier, it is anticipated that an investigation of the effect of inhibiting the formation of glucocerebroside and the toxic de-acylated derivative glucopsychosine, will be undertaken in patients with the neuronopathic forms of Gaucher disease.We have shown that bone-marrow transplantation causes a reduction of stored globotriaosylceramide in most of the organs and tissues of the murine model of Fabry disease. Bone-marrow stem and progenitor cells derived from patients with Fabry disease transduced with a retrovirus containing the human cDNA for alpha-galactosidase A are functionally corrected, and they express the enzyme for a long period of time. Moreover, the corrective alpha-galactosidase A is taken up by non-transduced bystander cells, and it is present in the circulation of experimental animals over an extended period. These experiments provide considerable incentive for gene therapy trials in patients with Fabry disease with transduced hematopoietic stem cells and bone-marrow mesenchymal stem cells. - Fabry Disease, Gaucher Disease; Inhibition of Sphingoglycolipid Formation; Gene Therapy - Human Subjects

在与英国牛津大学研究人员的一项合作研究中，我们正在研究小分子量抑制剂对三糖神经酰胺形成的影响，该抑制剂对 DMNB 和 NIDCR 科学家创建的法布里病小鼠类似物的影响。如果这些分子在该模型中被证明有效，那么它们的临床效果将在法布里病患者中进行评估。由于这些分子可以穿过血脑屏障，因此预计将在患有神经病性戈谢病的患者中进行抑制葡萄糖脑苷脂和有毒的去酰化衍生物葡萄糖精神苷形成的效果的研究。研究表明，骨髓移植导致法布里病小鼠模型的大多数器官和组织中储存的三酰神经酰胺减少。来自法布里病患者的骨髓干细胞和祖细胞被含有 α-半乳糖苷酶 A 的人类 cDNA 的逆转录病毒转导，其功能得到纠正，并且可以长时间表达该酶。此外，校正性α-半乳糖苷酶A被非转导的旁观者细胞吸收，并在实验动物的循环中长期存在。这些实验为使用转导的造血干细胞和骨髓间充质干细胞对法布里病患者进行基因治疗试验提供了相当大的动力。 - 法布里病、戈谢病；抑制鞘糖脂形成；基因治疗 - 人类受试者