Enzyme replacement in a canine model of Hurler syndrome.
Enzyme replacement in a canine model of Hurler syndrome.
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Hurler 综合征犬模型中的酶替代。
DOI：
10.1073/pnas.91.26.12937
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发表时间：
1994
影响因子：
11.1
通讯作者：
Neufeld,EF
中科院分区：
文献类型：
--
作者：
Shull,RM;Kakkis,ED;McEntee,MF;Kania,SA;Jonas,AJ;Neufeld,EF
Hurler 综合征（α-L-艾杜糖酸酶缺乏症）是一种严重的溶酶体贮积症，可能适合酶替代疗法。该疾病的犬模型的可用性和足够的校正酶供应允许持续 3 个月的治疗试验。重组人 α-L-艾杜糖醛酸酶，从稳定转染的中国仓鼠卵巢细胞系的分泌物中纯化至表观同质性，静脉内施用。对于纯合受影响的动物，剂量约为 1 mg。该酶以双相方式迅速从循环中消失，t1/2 分别为 0.9 和 19 分钟，并主要被肝脏吸收。在非常短的试验（12 天内施用七剂）之前和之后的肝脏活检显示，肝细胞和库普弗细胞中的溶酶体储存得到了显着的解决。在 3 个月的时间内，每周向三只受影响的动物施用酶后，肝脏和脾脏中的酶水平大致正常，肾脏和肺中的酶水平较低但显着，而脑、心脏瓣膜、心肌、软骨和角膜中的酶水平几乎检测不到（正常值的 0-5%）。许多组织的光镜和电子显微镜检查显示，肝、脾和肾小球中的溶酶体储存正常化，但大脑、心脏瓣膜或角膜没有改善。尽管接受治疗的狗产生了针对α-L-艾杜糖醛酸酶的补体激活抗体，但通过缓慢输注酶和术前用药可以预防临床症状。
The Hurler syndrome (alpha-L-iduronidase deficiency disease) is a severe lysosomal storage disorder that is potentially amenable to enzyme-replacement therapy. Availability of a canine model of the disease and a sufficient supply of corrective enzyme have permitted a therapeutic trial lasting 3 mo. Recombinant human alpha-L-iduronidase, purified to apparent homogeneity from secretions of a stably transfected Chinese hamster ovary cell line, was administered i.v. to homozygous affected animals in doses of approximately 1 mg. The enzyme rapidly disappeared from the circulation in a biphasic manner, with t1/2 of 0.9 and 19 min, respectively, and was taken up primarily by the liver. Biopsy of the liver before and after a very short trial (seven doses administered over 12 days) showed remarkable resolution of lysosomal storage in both hepatocytes and Kupffer cells. After weekly administration of enzyme to three affected animals over a period of 3 mo, the level of enzyme was about normal in liver and spleen, lower but significant in kidney and lung, and barely detectable (0-5% of normal) in brain, heart valves, myocardium, cartilage, and cornea. Light and electron microscopic examination of numerous tissues showed normalization of lysosomal storage in liver, spleen, and kidney glomeruli, but there was no improvement in brain, heart valves, or cornea. Even though the treated dogs developed complement-activating antibodies against alpha-L-iduronidase, clinical symptoms could be prevented by slow infusion of enzyme and premedication.