Laine M, Richter J, Fahlman C, Rapola J, Renlund M, Peltonen L, Karlsson S, Jalanko A
National Public Health Institute, Department of Human Molecular Genetics, Helsinki, Finland.
Exp Hematol. 1999 Sep;27(9):1467-74. doi: 10.1016/s0301-472x(99)00075-2.
Bone marrow transplantation has been shown to alleviate symptoms outside the CNS in many lysosomal storage diseases depending on the type and stage of the disease, but the effect on neurological symptoms is variable or still unclear. Aspartylglucosaminuria (AGU) is a lysosomal storage disease characterized by mental retardation, recurrent infections in childhood, hepatosplenomegaly and coarse facial features. Vacuolized storage lysosomes are found in all tissues of patients and uncleaved enzyme substrate is excreted in the urine. The recently generated AGU mouse model closely mimicks the human disease and serves as a good model to study the efficiency of bone marrow transplantation in this disease.
Eight-week-old AGU mice were lethally irradiated and transplanted with bone marrow from normal donors. The AGA enzyme activity was measured in the liver and the brain and the degree of correction of tissue pathology was analyzed by light and electron microscopy. Reverse bone marrow transplantation (AGU bone marrow to wild-type mice) was also performed.
Six months after transplantation the AGA enzyme activity was 13% of normal in the liver, but only 3% in the brain. Tissue pathology was reversed in the liver and the spleen, but not in the brain and the kidney. The urinary excretion of enzyme substrate was diminished but still detectable. No storage vacuoles were found in the tissues after reverse transplantation, but subtle excretion of uncleaved substrate was detected in the urine.
Liver and spleen pathology of AGU was corrected by bone marrow transplantation, but there was no effect on lysosomal accumulation in the CNS and in the kidneys.
骨髓移植已被证明在许多溶酶体贮积病中可缓解中枢神经系统以外的症状，这取决于疾病的类型和阶段，但对神经症状的影响则各不相同或仍不明确。天冬氨酰葡糖胺尿症（AGU）是一种溶酶体贮积病，其特征为智力发育迟缓、儿童期反复感染、肝脾肿大及面部特征粗糙。在患者的所有组织中均发现有含空泡的贮积溶酶体，且未裂解的酶底物随尿液排出。最近构建的AGU小鼠模型与人类疾病极为相似，是研究该疾病中骨髓移植效果的良好模型。
对8周龄的AGU小鼠进行致死性照射，然后移植正常供体的骨髓。测定肝脏和大脑中的AGA酶活性，并通过光学显微镜和电子显微镜分析组织病理学的纠正程度。还进行了反向骨髓移植（将AGU骨髓移植到野生型小鼠）。
移植后6个月，肝脏中的AGA酶活性为正常水平的13%，但大脑中仅为3%。肝脏和脾脏的组织病理学得到了逆转，但大脑和肾脏未出现逆转。酶底物的尿排泄量减少，但仍可检测到。反向移植后，组织中未发现贮积空泡，但尿液中检测到了未裂解底物的微量排泄。
骨髓移植纠正了AGU的肝脏和脾脏病理改变，但对中枢神经系统和肾脏中的溶酶体积聚没有影响。
