ENZYME REPLACEMENT THERAPY FOR MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII
ENZYME REPLACEMENT THERAPY FOR MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII
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DOI：
10.1172/jci117237
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发表时间：
1994-06-01
影响因子：
15.9
通讯作者：
BIRKENMEIER, EH
中科院分区：
文献类型：
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作者：
SANDS, MS;VOGLER, C;BIRKENMEIER, EH
重组小鼠β -葡萄糖醛酸酶静脉注射给新生的粘多糖病VII型小鼠（RIPS VII），可迅速从循环中清除并定位于许多组织。在这里，我们确定了注射酶的组织分布，并描述了其对6周龄MPS VII小鼠的组织病理学影响，这些小鼠在5周龄时注射一次28,000 U重组β -葡糖醛酸酶，或者从出生开始每周注射6次28,000 U。将这些小鼠与未处理的6周龄RIPS VII小鼠进行比较。单次注射可降低小鼠体内溶酶体膨胀。红组织巨噬细胞系统。多次注射MPS VII小鼠的肝脏、脾脏和肾脏β -葡糖醛酸酶水平分别为正常水平的27.8%、3.5%和3.3%。大脑检测到β -葡糖醛酸酶，范围为正常的2.0-12.1%。与未治疗的MPS VII小鼠相比，脑、脾、肝和肾中α -半乳糖苷酶和β -己糖苷酶的继发性升高降低。尽管软骨细胞、胶质细胞和一些神经元未见改善，但骨骼的临床和病理证据较少，脑膜和某些神经元组的溶酶体储存减少。这些数据表明，在新生MPS VII小鼠中开始的重组β -葡糖醛酸酶治疗为大多数组织提供了酶，并在生命的前6周显著减少或阻止溶酶体储存的积累。在生命后期开始治疗是否能达到这种程度的矫正还有待确定。
Recombinant mouse beta-glucuronidase administered intravenously to newborn mice with mucopolysaccharidosis type VII (RIPS VII) is rapidly cleared from the circulation and localized in many tissues. Here we determine the tissue distribution of injected enzyme and describe its effects on the histopathology in 6-wk-old MPS VII mice that received either one injection of 28,000 U recombinant beta-glucuronidase at 5 wk of age or received six injections of 28,000 U given at weekly intervals beginning at birth. These mice were compared with untreated 6-wk-old RIPS VII mice. The single injection decreased lysosomal distention in the fi?red tissue macrophage system. MPS VII mice that received multiple injections had 27.8, 3.5, and 3.3% of normal le,els of beta-glucuronidase in liver, spleen, and kidney, respectively. Brain had detectable beta-glucuronidase, ranging from 2.0-12.1% of normal. Secondary elevations of alpha-galactosidase and beta-hexosaminidase in brain, spleen, liver, and kidney were decreased compared with untreated MPS VII mice. Although no improvement was observed in chondrocytes, glia, and some neurons, the skeleton had less clinical and pathological evidence of disease and the brain had reduced lysosomal storage in meninges and selected neuronal groups. These data show that recombinant beta-glucuronidase treatment begun in newborn MPS VII mice provides enzyme to most tissues and significantly reduces or prevents the accumulation of lysosomal storage during the first 6 wk of life. Whether therapy begun later in life ran achieve this level of correction remains to be established.