Treatment of Inherited Metabolic Diseases by Bone Marrow Transplantation

最近，骨髓移植被认为是治疗某些先天性代谢缺陷的一种形式。从我们对尼曼-皮克小鼠的实验来看，骨髓移植并没有改善神经系统的表现。但脾脏中鞘磷脂和胆固醇的积累明显减少。由于没有观察到神经系统的改善，这可能归因于一些可能的原因，例如血脑屏障的存在，阻止白细胞进入大脑的必要区域。为探讨骨髓移植（BMT）治疗某些遗传代谢性疾病的机制，采用Percholl梯度离心法对骨髓移植前后的Niemann-Pick小鼠肝、脑进行了亚细胞分级。骨髓移植前Niemann-Pick小鼠肝、脑溶酶体中酸性鞘磷脂酶活性明显降低，鞘磷脂和胆固醇含量明显升高。另一方面，BMT后，酸性鞘磷脂酶活性显著增加，胆固醇和鞘磷脂在溶酶体中的积累减少。然而，生化程序，未能证明任何变化的酸性鞘磷脂酶的活性和脂质含量从大脑的溶酶体后BMT在Niemann-Pick小鼠。在接下来的研究中，我们检查了从Niemann-Pick小鼠的造血细胞移植到近交系正常小鼠的生化和病理学效应，并从肝脏和脑中分离溶酶体。肝脏溶酶体中酸性鞘磷脂酶活性略有下降，脂质含量增加。这项研究是第一次报告的积极改变酶活性和脂质含量的溶酶体从肝脏的尼曼-匹克小鼠骨髓移植后。

Recently, bone marrow grafts have been considered as one form of treatment for certain inborn errors of metabolism. From our experiment with Niemann-Pick mice, the bone marrow graft did not improve the neurological manifestation. However, the accumulation of sphingomyelin and cholesterol in the spleen was decreased remarkably. Since no neurological improvement was noticed, this could be ascribed to some possible causes, such as the existance of blood-brain-barriers which prohibit the leucocytes from entering the necessary areas of the brain. In order to investigate therapeutic mechanism of bone marrow transplantation (BMT) in certain inherited metabolic diseases, subcellular fractionation of the liver and brain in Niemann-Pick mice before and after BMT was carried out by percholl gradient centrifugation. The marked decrease of acid sphingomyelinase activities and increase of sphingomyelin and cholesterol at the lysosomal fraction of the liver and brain in Niemann-Pick mice before BMT was noticed. On the other hand, after BMT, a significant increase of acid sphingomyelinase activity and a decrease of cholesterol and sphingomyelin accumulation in lysosome were demonstrated. Biochemical procedures, however, failed to demonstrate any change of acid sphingomyelinase activity and lipid contents in lysosome from the brain after BMT in Niemann-Pick mice. In the next study we examined the biochemical and pathological effects of transplanting haematopoietic cells from Niemann-Pick mice into inbred normal mice, and isolation of the lysosome from the liver and brain was carried out. A slight decrease of acid sphingomyelinase activity and a increase of lipid contents in the lysosome from the liver were noticed. This study is the first report of positive alterations in enzyme activity and lipid contents in the lysosome from the liver of the Niemann-Pick mice after BMT.