BASIC STUDIES ON ETIOLOGY, PATHOGENESIS & THERAPY OF METABOLIC STORAGE DISORDERS

病因、发病机制基础研究

• 批准号: 6432947
• 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/6432947
• 关键词: Fabry's disease; Gaucher's disease; Tay Sachs disease; clinical research; disease /disorder etiology; enzyme therapy; glucosylceramidase; human subject; human therapy evaluation; inborn lysosomal enzyme disorder; intravenous administration; myoclonus epilepsy; pathologic process

Fabry disease: We have explored several therapeutic strategies to treat patients with Fabry disease using the alpha-galactosidase A knock-out animal model of Fabry disease created by the Developmental and Metabolic Neurology Branch, We found that bone marrow stem and progenitor cells that had been transduced with a retroviral vector containing the alpha-galactosidase A gene resulted in the secretion of significant amounts of this enzyme into the blood of recipient animals. This demonstration indicated that the enzyme might be available to all of the organs and tissues of the animal. This observation was followed by studies on the effect of infusions of the transduced cells on the quantity of ceramidetrihexoside in the organs of the murine analog. The amount of accumulated lipid was significantly reduced following administration of the gene-corrected cells. Together, these findings provide encouragement for the exploration of gene therapy for Fabry disease. Another approach under consideration for the treatment of patients with this disorder is inhibition of the synthesis of ceramidetrihexoside. This strategy has been called"substrate depletion". When immortalized lymphoblasts derived from patients with Fabry disease were treated with a potent inhibitor of ceramidetrihexoside synthesis developed by collaboratorsat the University of Michigan, we observed that the quantity of ceramidetrihexoside was significantly reduced. This investigation was followed by an examination of the effect of a similar inhibitor of ceramidetrihexoside synthesis in the mouse model of Fabry disease. We observed striking reductions in the quantities of this lipid in all of the major organs of the treated mice. These findings suggest that substrate depletion may have a role in the management of Fabry disease, alone, or perhaps in concert with enzyme replacement or gene therapy. Mucolipidosis IV. We have discovered the gene that is mutated in patients with this devastating neurogenetic disorder. It codes for a previously unknown ion channel protein. The condition is therefore properly classified as a novel channelopathy. This discovery is essential for the development of rational approaches to the therapy of this condition. An immediate benefit from the discovery is the ability to provide genetic counseling to a number of families in which this disorder occurs.

法布里病：我们已经探索了几种使用α-半乳糖苷酶治疗法布里病患者的治疗策略。发育和代谢神经病学分支创建的法布里病敲除动物模型，我们发现骨髓干细胞和祖细胞用含有α-半乳糖苷酶A基因的逆转录病毒载体转导，导致大量这种酶分泌到受体动物的血液中。这一证明表明该酶可能适用于动物的所有器官和组织。随后研究了转导细胞的输注对小鼠类似物器官中神经酰胺三己糖苷含量的影响。施用基因校正细胞后，积累的脂质量显着减少。总之，这些发现为法布里病基因治疗的探索提供了鼓励。正在考虑治疗患​​有这种疾病的患者的另一种方法是抑制神经酰胺三己糖苷的合成。该策略被称为“底物耗尽”。当来自法布里病患者的永生化淋巴母细胞用密歇根大学合作者开发的神经酰胺三己糖苷合成的有效抑制剂治疗时，我们观察到神经酰胺三己糖苷的数量显着减少。这项研究随后检查了类似的神经酰胺三己糖苷合成抑制剂在法布里病小鼠模型中的作用。我们观察到接受治疗的小鼠所有主要器官中这种脂质的数量显着减少。这些发现表明，底物消耗可能在法布里病的治疗中发挥作用，单独使用或与酶替代或基因治疗结合使用。粘脂沉积症 IV.我们发现了患有这种破坏性神经遗传性疾病的患者体内发生突变的基因。它编码一种以前未知的离子通道蛋白。因此，这种情况被正确地归类为一种新型通道病。这一发现对于开发治疗这种疾病的合理方法至关重要。这一发现的直接好处是能够为许多发生这种疾病的家庭提供遗传咨询。