Mouse Models of Inherited Metabolic Disorders

遗传性代谢紊乱的小鼠模型

• 批准号: 6432039
• 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/6432039
• 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

法布里病是一种致命的 X 连锁隐性代谢性疾病，由溶酶体酶 α-半乳糖苷酶 A (AGA) 活性缺陷引起。在受影响的半合子男性中，血管内皮细胞和平滑肌细胞的溶酶体中底物​​的逐渐沉积导致闭塞性血管疾病。迄今为止，还没有针对这种情况的具体治疗方法。酶替代和基因疗法都在考虑之中，但在人体中进行这些试验将是困难且耗时的。我们开发了法布里小鼠模型，这对于开发此类治疗方案非常有价值。该小鼠模型是通过基因打靶破坏 AGA 基因组位点而生成的。这些小鼠缺乏 AGA 活性，没有任何总体表型，但表现出亚临床异常，例如目标组织中的同心层状包涵体。衰老研究揭示了心脏组织中底物的逐渐积累和功能变化。用野生型小鼠的骨髓对法布里小鼠进行骨髓移植，纠正了大多数靶组织的代谢缺陷，表明了其在临床领域的价值。对这些小鼠的骨髓单核细胞使用逆转录病毒基因治疗方法并将其移植到 Fabry 小鼠体内，结果表明 BMT 后 26 周，移植小鼠的大多数靶组织中 AGA 活性增加，脂质底物水平降低。使用腺载体的类似研究是 cu