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

在与英国牛津大学的研究人员的合作研究中，我们正在研究Globotriaosylceramide在DMNB和NIDCR中科学家创建的Fabry疾病的鼠类类似物中的小分子量抑制剂的影响。如果这些分子在该模型中有效，则将在Fabry病患者中评估它们的临床作用。由于这些分子可以越过血脑屏障，因此可以预期，对抑制糖酮糖苷形成的作用和有毒的脱离衍生化的葡萄糖苷的作用将在神经统治形式的患者中进行，我们已经表明，Gaucher疾病的神经性形式。 Fabry病鼠模型的组织。骨髓茎和祖细胞衍生自含有逆转录病毒的Fabry疾病患者，其中含有人cDNA的α-半乳糖苷酶A的逆转录病毒在功能上得到校正，并且很长一段时间内表达酶。此外，矫正α-半乳糖苷酶A被非转导的旁观者细胞吸收，并且在长时间内存在于实验动物的循环中。这些实验为患有转导造血干细胞和骨髓间充质干细胞的Fabry疾病患者的基因治疗试验提供了相当大的动力。 - 法布里病，高雪病；抑制鞘脂的形成；基因疗法 - 人类受试者