MOUSE MODELS OF INHERITED METABOLIC DISORDERS

遗传性代谢紊乱的小鼠模型

• 批准号: 6289702
• 负责人: Ashok B. KULKARNI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 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/6289702
• 关键词: Fabry's disease; alpha galactosidase; disease /disorder model; embryonic stem cell; enzyme therapy; gene targeting; gene therapy; laboratory mouse; model design /development

Fabry disease is a fatal X-linked recessive metabolic disorder resulting from the deficient activity of the lysosomal enzyme, a-galactosidase A (AGA). In affected hemizygous males, the progressive deposition of substrate in lysosomes of vascular endothelial and smooth muscle cells causes occlusive vascular disease. To date, there is no specific treatment for this condition. Both enzyme replacement and gene therapy are under consideration, but carrying out these trials in human will be difficult and time-consuming. We have developed Fabry mouse model which will be valuable to develop such therapeutic regimes. This mouse model was generated by disrupting AGA genomic locus by gene targeting. These mice were deficient in AGA activity without any gross phenotype but displayed subclinical abnormalities such as concentric lamellar inclusions in the target tissues. Aging studies revealed progressive accumulation of the substrate and functional changes in the cardiac tissues. Bone marrow transplantation of the Fabry mice with bone marrow from wild type mice corrected the metabolic defects in most of the target tissues indicating its value in the clinical domain. Using retroviral gene therapy approach on bone marrow mononuclear cells from these mice and transplanting them into the Fabry mice indicated increase in the AGA activity and reduction in the lipid substrate levels in most of the target tissues of the transplanted mice 26 weeks post BMT. Similar studies using adeno vectors are cu

Fabry病是由于溶酶体酶（A-galactosidase a（AGA））的活性不足而导致的致命X连锁隐性代谢疾病。在受影响的半细胞雄性中，底物在血管内皮和平滑肌细胞的溶酶体中的逐渐沉积会导致闭塞性血管疾病。迄今为止，对于这种情况还没有特定的治疗方法。正在考虑酶的替代和基因治疗，但是在人类中进行这些试验将很困难且耗时。我们已经开发了Fabry Mouse模型，该模型对于开发此类治疗方案很有价值。该小鼠模型是通过通过基因靶向破坏AGA基因组基因座来产生的。这些小鼠缺乏AGA活性，没有任何粗大表型，但显示出亚临床异常，例如目标组织中的同心层状包含物。衰老研究表明，底物的逐步积累和心脏组织中的功能变化。在野生型小鼠的骨髓对Fabry小鼠的骨髓移植纠正了大多数目标组织中的代谢缺陷，表明其在临床结构域中的值。使用这些小鼠的骨髓单核细胞上的逆转录病毒基因治疗方法，并将其移植到Fabry小鼠中，表明在BMT 26周移植小鼠的大多数目标组织中，AGA活性的增加和脂质底物水平的降低。使用Adeno载体的类似研究是Cu