IN UTERO TRANSPLANTATION FOR LYSOSOMAL STORAGE DISEASE

出生后骨髓或外周血干细胞移植可以 有效地治疗许多涉及血细胞的遗传性疾病，但 并不是所有人都能得到，因为它成本高，风险中等， 以及缺乏合适的造血干细胞捐赠者。AS 重要的是，在一些疾病中，例如溶酶体储存障碍， 神经毒性是通过出生发生的，这是不可逆的 移植。研究人员计划研究宫内疗法。 猫患阿尔法甘露糖沉着症。除了移植造血干细胞 从成年猫到家猫胎儿的细胞，他们提出了两种新的 巨噬细胞前体细胞宫内移植途径 和子宫内基因转移(用FeLV假型逆转录病毒载体 包含标记基因和/或MANB基因)。调查人员还将 小鼠巨噬细胞在ROSA26体内植入的动力学研究 移植模型，鉴定急性髓系白血病的直接前体细胞 脑中的小胶质细胞、肝脏中的枯否细胞和肺泡巨噬细胞 在肺里。研究人员将定义细胞机制， 调解寄宿。在这个小鼠模型中的实验结果将 在α-甘露聚糖症宫内移植研究中的应用 在猫身上。调查人员希望这些研究将提供 治疗溶酶体储存障碍的替代方法。

Post-natal marrow or peripheral blood stem cell transplantation can effectively treat many genetic disorders which involve blood cells, but is not universally available because of its high cost, moderate risk, and the lack of suitable donors of hematopoietic stem cells. As importantly, in some diseases, such as the lysosomal storage disorders, neurologic toxicity occurs by birth, which is not reversible by transplantation. The investigators plan to study the in utero therapy of alpha-mannosidosis in cats. Besides transplanting hematopoietic stem cells from adult cats to domestic cat fetuses, they propose two novel approaches, the in utero transplantation of macrophage precursor cells and in utero gene transfer (with FeLV-pseudotyped, retroviral vectors containing marker genes and/or MANB cDNA). The investigators will also study the kinetics of tissue macrophage engraftment in a murine ROSA26 transplantation model, to identify the immediate precursor cell of microglia in brain, Kuppffer cells in liver, and alveolar macrophages in lung. The investigators will define the cellular mechanisms which mediate lodgment. The results of experiments in this murine model will be applied in the in utero transplantation studies of alpha-mannosidosis in cats. The investigators are hopeful that these studies will provide alternative approaches for the therapy of lysosomal storage disorders.