MOUSE MODELS OF INHERITED METABOLIC DISORDERS

法布里病是一种致死性X连锁隐性代谢紊乱，由溶酶体酶α-半乳糖苷酶A（阿加）活性缺陷引起。在受影响的半合子雄性中，底物在血管内皮细胞和平滑肌细胞的溶酶体中进行性沉积导致闭塞性血管疾病。到目前为止，还没有针对这种情况的具体治疗方法。酶替代和基因治疗都在考虑之中，但在人体上进行这些试验将是困难和耗时的。我们已经开发了Fabry小鼠模型，这将是有价值的开发这样的治疗方案。该小鼠模型通过基因打靶破坏阿加基因组位点而产生。这些小鼠缺乏阿加活性，没有任何大体表型，但显示亚临床异常，如靶组织中的同心层状包涵体。衰老研究揭示了底物的进行性积累和心脏组织的功能变化。用野生型小鼠的骨髓移植法布雷病小鼠，纠正了大多数靶组织中的代谢缺陷，表明其在临床领域的价值。对来自这些小鼠的骨髓单个核细胞使用逆转录病毒基因治疗方法并将其移植到Fabry小鼠中，表明BMT后26周移植小鼠的大多数靶组织中的阿加活性增加和脂质底物水平降低。使用腺病毒载体的类似研究是cu

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