Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis.
Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis.
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DOI：
10.1016/j.ymgme.2009.12.002
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发表时间：
2010-04
影响因子：
3.8
通讯作者：
Hofmann SL
中科院分区：
文献类型：
--
作者：
Lu JY;Hu J;Hofmann SL
婴儿神经元蜡样质脂褐质沉积症（INCL，也称为Haltia-Santavuori病）是一种婴儿和儿童的溶酶体储存疾病，其特征在于失明、癫痫发作和进行性神经退行性过程。最近的临床试验涉及神经干细胞和针对中枢神经系统的基因治疗;然而，酶替代疗法从未得到解决。在本文中，我们描述了在中国人卵巢（CHO）细胞中通过标准方法生产人重组PPT 1（INCL中的缺陷酶）。通过甘露糖6-磷酸受体结合（80%结合）评估，该酶主要是甘露糖6-磷酸化的，并被永生化的患者淋巴母细胞迅速吸收，其中证明了PPT底物的清除（过夜孵育后EC 50为0.25 nM）。当静脉注射到PPT 1缺陷小鼠，重组人PPT 1从血浆中的清除是快速的，半衰期为10分钟。大部分注射剂量分布到肾脏和肝脏和潜在的纠正水平也观察到在心脏，肺和脾脏。根据其他静脉内给药溶酶体酶的经验，脑摄取极轻微。这种酶可以作为中枢神经系统定向治疗的辅助药物，并可以作为改善大脑递送的修饰的起点。
Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC50 of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.
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影响因子：
3.8
作者：
Hemsley, Kim M.;King, Barbara;Hopwood, John J.
通讯作者：
Hopwood, John J.
DOI：
10.1073/pnas.0506892102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Vogler, C;Levy, B;Sly, WS
通讯作者：
Sly, WS
影响因子：
11.2
作者：
van Diggelen, OP;Thobois, S;Voznyi, YV
通讯作者：
Voznyi, YV
影响因子：
15.9
作者：
Das, AK;Becerra, CHR;Hofmann, SL
通讯作者：
Hofmann, SL
影响因子：
3.5
作者：
Blanz, Judith;Stroobants, Stijn;Saftig, Paul
通讯作者：
Saftig, Paul