Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis
Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis
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DOI：
10.1016/j.ymgme.2012.05.009
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发表时间：
2012-09-01
影响因子：
3.8
通讯作者：
Hofmann, Sandra L.
中科院分区：
文献类型：
--
作者：
Hu, Jie;Lu, Jui-Yun;Hofmann, Sandra L.
PPT 1相关神经元蜡样质脂褐质沉积症（NCL）是一种由可溶性溶酶体酶棕榈酰蛋白硫酯酶-1（PPT 1）缺乏引起的溶酶体贮积症。酶替代疗法（ERT）以前没有在临床前动物模型中进行过研究。纯合子PPT 1基因敲除小鼠重现了该疾病的已知特征，在5个月大时出现运动功能障碍的迹象，并在8个月左右死亡。在本研究中，用纯化的重组PPT 1（0.3 mg，对于25 g小鼠，对应于12 mg/kg或180 U/kg）每周静脉内施用1）从出生时;或2）从8周龄开始治疗PPT 1敲除小鼠。该治疗令人惊讶地耐受良好，并且既没有观察到过敏反应也没有观察到抗体形成。在出生后接受治疗的小鼠中，存活时间从236天增加到271天（p
PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death by around 8 months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) from birth: or 2) beginning at 8 weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271 days (p