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错误的一种形式。从我们对Niemann-Pick小鼠的实验来看，骨髓移植并没有改善神经系统的表现。脾脏中鞘磷脂和胆固醇的积累明显减少。由于没有注意到神经系统的改善，这可以归因于一些可能的原因，例如血脑屏障的存在，它禁止白细胞进入大脑的必要区域。为了探讨骨髓移植（BMT）治疗某些遗传性代谢性疾病的机制，采用percholl梯度离心法对Niemann-Pick小鼠骨髓移植前后的肝脏和大脑进行亚细胞分离。BMT前Niemann-Pick小鼠肝脏和脑溶酶体部分酸性鞘磷脂酶活性明显降低，鞘磷脂和胆固醇水平明显升高。另一方面，BMT后酸性鞘磷脂酶活性显著升高，溶酶体中胆固醇和鞘磷脂积累显著降低。然而，生化程序未能证明Niemann-Pick小鼠BMT后脑内酸性鞘磷脂酶活性和溶酶体脂质含量有任何变化。在接下来的研究中，我们研究了将Niemann-Pick小鼠的造血细胞移植到近亲繁殖的正常小鼠体内的生化和病理效果，并从肝脏和大脑中分离溶酶体。肝脏酸性鞘磷脂酶活性轻微下降，溶酶体脂质含量增加。本研究首次报道了BMT后Niemann-Pick小鼠肝脏溶酶体酶活性和脂质含量的阳性变化。

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.