Enzyme replacement therapy for murine hypophosphatasia
Enzyme replacement therapy for murine hypophosphatasia
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DOI：
10.1359/jbmr.071213
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发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Whyte, Michael P.
中科院分区：
文献类型：
--
作者：
Millan, Jose Luis;Narisawa, Sonoko;Whyte, Michael P.
介绍：低磷酸酶（HPP）是一种先天性代谢错误，以佝偻病或骨软化症为特征，由编码组织非特异性碱性磷酸酶（TNALP）同工酶的基因发生功能丧失突变引起。因此，这种酶的天然底物在细胞外积累，包括无机焦磷酸盐（PP），一种矿化抑制剂，和吡哆醛5'-磷酸（PLP），一种维生素B-6的辅助因子形式。患有婴儿型HPP的婴儿通常死于严重的佝偻病，有时还会出现高钙血症和维生素b -6依赖性癫痫发作。没有确定的治疗方法。材料和方法：人类TNALP采用生物工程技术，C端由人IgG的Fc区延伸一步纯化，十天冬氨酸序列（D-10）用于靶向矿化组织（sALP-FcD(10)）。tnalp缺失小鼠（Akp2(-/-)）是一种很好的婴儿HPP模型，从出生开始使用sALP-FcD10治疗。短期和长期疗效研究包括每天一次皮下注射1、2或8.2 mg/kg sALP-FcD(10)，分别持续15、19和15或52天。我们通过x线摄影、mu CT和组织形态学测量评估了存活率和生长率、sALP-FcD（10）活性的循环水平、钙、PPi和吡哆醛，以及骨骼和牙齿的表现。结果：接受高剂量sALP-FcD（10）治疗的Akp2（-/-）小鼠生长正常，外观良好，无骨牙疾病和癫痫。血浆钙、PPi和吡哆醛浓度保持在正常范围内。我们没有发现明显骨骼或牙齿疾病的证据。结论：在Akp2（-/-）小鼠中，使用骨靶向、重组形式的人类TNALP替代酶可预防婴儿HPP。
Introduction: Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PP), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), a co-factor form of vitamin B-6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B-6-dependent seizures. There is no established medical treatment.Materials and Methods: Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D-10) for targeting to mineralizing tissue (sALP-FcD(10)). TNALP-null mice (Akp2(-/-)), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD(10) for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD(10) activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, mu CT, and histomorphometry.Results: Akp2(-/-) mice receiving high-dose sALP-FcD(10) grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease.Conclusions: Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2(-/-) mice.