TREATMENT OF ADENOSINE-DEAMINASE DEFICIENCY WITH POLYETHYLENE-GLYCOL MODIFIED ADENOSINE-DEAMINASE
TREATMENT OF ADENOSINE-DEAMINASE DEFICIENCY WITH POLYETHYLENE-GLYCOL MODIFIED ADENOSINE-DEAMINASE
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DOI：
10.1056/nejm198703053161005
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发表时间：
1987-03-05
影响因子：
158.5
通讯作者：
ABUCHOWSKI, A
中科院分区：
文献类型：
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作者：
HERSHFIELD, MS;BUCKLEY, RH;ABUCHOWSKI, A
我们用聚乙二醇偶联物修饰的牛腺苷脱氨酶治疗两例腺苷脱氨酶缺乏症和严重联合免疫缺陷病患儿。修饰后的酶在肌肉注射后吸收迅速，在血浆中的半衰期为48~72小时。每周剂量约为每公斤体重15U，可将血浆腺苷脱氨酶活性维持在正常受试者红细胞腺苷脱氨酶活性水平的两到三倍。腺苷脱氨酶缺乏的主要生化后果几乎完全逆转。在红细胞中，腺苷核苷酸增加，脱氧腺苷核苷酸减少到总腺嘌呤核苷酸的0.5%以下。经脱氧腺苷灭活的S-腺苷同型半胱氨酸水解酶在红细胞和有核骨髓细胞中活性恢复到正常水平。未见毒性反应和过敏反应。对每个患者的细胞免疫功能的体外测试显示，随着循环T淋巴细胞的增加，患者的细胞免疫功能显著改善。临床改善表现为无感染和体重恢复增加。我们的结论是，从疗效、方便和安全的角度来看，聚乙二醇化的腺苷脱氨酶治疗腺苷缺乏症比红细胞输注更可取。在其他遗传性代谢性疾病中，累积的代谢物与血浆保持平衡的患者可以从适当的聚乙二醇介导酶治疗中受益。
We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme as rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses of approximately 15 U per kilogram of body weight maintained plasma adenosine deaminase activity at two to three times the level of erythrocyte adenosine deaminase activity in normal subjects. The principal biochemical consequences of adenosine deaminase deficiency were almost completely reversed. In erythrocytes, adenosine nucleotides increased and deoxyadenosine nucleotides decreased to less than 0.5 percent of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of the cellular immune function of each patient showed marked improvement, along with an increase in circulating T lymphocytes. Clinical improvement was indicated by absence of infection and resumption of weight gain. We conclude that the standpoints of efficacy, convenience, and safety, polyethylene glycol-modified adenosine deaminase is preferable to red-cell transfusion as a treatment for adenosine deficiency. Patients with other inherited metabolic diseases in which accumulated metabolites equilibrate with plasma could benefit from treatment with the appropriate polyethylene glycol-mediated enzyme.