In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of β-glucuronidase can delay onset of clinical signs
In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of β-glucuronidase can delay onset of clinical signs
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DOI：
10.1182/blood.v97.6.1625
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发表时间：
2001-03-15
期刊：
影响因子：
20.3
通讯作者：
Wolfe, JH
中科院分区：
文献类型：
--
作者：
Casal, ML;Wolfe, JH
患有由β-葡萄糖醛酸酶（GUSB）缺乏引起的溶酶体贮积病粘多糖贮积症（MPS）VII的小鼠在出生时就有疾病迹象，骨髓移植（BMT）或逆转录病毒载体介导的基因转移到造血干细胞中可以部分纠正成年小鼠的疾病，出生时进行的BMT可以带来更好的临床结果。因此，子宫内治疗可能会导致进一步的改善，然而，这必须在没有细胞消融的情况下完成，并且供体细胞不具有比宿主细胞竞争性的再增殖优势。在子宫内移植带有逆转录病毒载体标记的同基因胎儿肝脏造血干细胞，或从转基因中持续表达高水平人GUSB的同种异体供体细胞，在成人中的植入率仅为约0.1%。干细胞和祖细胞的免疫亲和力富集 5 至 10 倍，导致 2 个月龄时 GUSB 活性显着升高，但到 6 个月时，植入率约为 0.1%。进一步增加干细胞和祖细胞数量的尝试对受体来说是有害的。然而，在 MPS VII 胎儿生命的前 2 个月内表达的 GUSB 可能会延迟疾病明显体征的出现。这表明，从胎儿生命开始的一些正常酶活性的表达可能提供减缓疾病进展的可能性，直到可以完成更明确的产后移植或基因转移到干细胞。 （血液。2001；97：1625-1634）(C) 2001 年，美国血液学会。
Mice with the lysosomal storage disease mucopolysaccharidosis (MPS) VII, caused by a deficiency of beta -glucuronidase (GUSB), have signs of disease present at birth, Bone marrow transplantation (BMT) or retroviral vector-mediated gene transfer into hematopoietic stem cells can partially correct the disease in adult mice, and BMT performed at birth results in a better clinical outcome. Thus, treatment in utero may result in further improvement, However, this must be done without cyto-ablation, and the donor cells do not have a competitive repopulating advantage over host cells. Transplantation in utero of either syngeneic fetal liver hematopoietic stem cells marked with a retroviral vector, or allogeneic donor cells that constitutively express high levels of human GUSB from a transgene, resulted in only about 0.1% engraftment in the adult. Immune-affinity enrichment of stem and progenitor cells of 5- to 10-fold resulted in significantly higher GUSB activities at 2 months of age, but by 6 months engraftment was about 0.1%. Attempts to further increase the number of stem and progenitor cells were deleterious to the recipients. Nevertheless, GUSB expressed during the first 2 months of life in MPS VII fetuses could delay the onset of overt signs of disease. This suggests that the expression of some normal enzyme activity beginning in fetal life may offer the possibility of slowing the progression of the disease until more definitive postnatal transplantation or gene transfer to stem cells could be accomplished. (Blood. 2001;97:1625-1634) (C) 2001 by The American Society of Hematology.