Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI
Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI
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DOI：
10.1172/jci119208
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发表时间：
1997-02-15
影响因子：
15.9
通讯作者：
Hopwood, JJ
中科院分区：
文献类型：
--
作者：
Crawley, AC;Niedzielski, KH;Hopwood, JJ
我们报告的证据表明，酶替代疗法的剂量反应效应的粘多糖样变性VI型猫从出生，在临床，生化和组织病理学水平。每周静脉注射1和5 mg/kg重组人N-乙酰半乳糖胺-4-硫酸酯酶的猫体重更重，更灵活，脊髓压迫大大减轻或无脊髓压迫，尿糖胺聚糖水平几乎正常。心脏瓣膜、主动脉、皮肤、硬脑膜、肝脏和脑血管周围细胞中的溶酶体储存接近正常或完全逆转。在软骨或角膜中未观察到溶酶体空泡化减少;然而，在一些给药猫中，关节软骨较薄，外耳道较大。给药猫的退行性关节变化没有明显延迟。5 - 6个月时，骨骼病理学减轻，骨尺寸更正常，骨密度更均匀，骨小梁模式在X线片上清晰可见;然而，1和5 mg/kg剂量率之间的差异无法明确区分。在0.2 mg/kg剂量下，检查的大多数参数均未显著改变疾病。中期粘多糖沉积症VI型胎仔检查的所有组织中均存在溶酶体蓄积，并且从出生起范围和严重程度迅速增加。
We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.