REPLACEMENT THERAPY FOR INHERITED ENZYME DEFICIENCY - MACROPHAGE-TARGETED GLUCOCEREBROSIDASE FOR GAUCHERS-DISEASE
REPLACEMENT THERAPY FOR INHERITED ENZYME DEFICIENCY - MACROPHAGE-TARGETED GLUCOCEREBROSIDASE FOR GAUCHERS-DISEASE
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DOI：
10.1056/nejm199105233242104
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发表时间：
1991-05-23
影响因子：
158.5
通讯作者：
YU, KT
中科院分区：
文献类型：
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作者：
BARTON, NW;BRADY, RO;YU, KT
研究背景和方法。高雪氏病是最常见的鞘磷脂储存障碍，由葡萄糖脑苷酸酶(葡萄糖神经酰胺酶)缺乏引起。1966年，酶替代被提出作为治疗这种疾病的一种策略。为了评估这种方法的临床效果，我们将巨噬细胞靶向的人胎盘葡萄糖脑苷酶(每公斤体重60IU，持续9至12个月)注入12例脾完整的1型高雪病患者。在部分试验期间，两名患者(儿童)的输液频率增加到每周一次，因为他们患有临床侵袭性疾病。所有12例患者的血红蛋白浓度均升高，7例患者的血小板计数升高。10例患者在试验期间血清酸性磷酸酶活性下降，9例患者的血浆葡萄糖脑苷水平下降。治疗6个月后所有患者的脾体积均缩小，5例患者的肝脏体积减小。在三名患者中发现了骨骼改善的早期迹象。酶输注耐受性良好，未出现外源性酶抗体。静脉注射巨噬细胞靶向的葡萄糖脑苷酶在1型高谢病患者中产生了客观的临床改善。血液学和内脏对酶替代的反应比骨骼反应发展得更快。
Background and Methods. Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease.Results. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed.Conclusions. Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.