Intracerebroventricular delivery of glucocerebrosidase reduces substrates and increases lifespan in a mouse model of neuronopathic Gaucher disease
Intracerebroventricular delivery of glucocerebrosidase reduces substrates and increases lifespan in a mouse model of neuronopathic Gaucher disease
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DOI：
10.1016/j.expneurol.2010.07.023
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发表时间：
2010-10-01
影响因子：
5.3
通讯作者：
Scheule, R. K.
中科院分区：
文献类型：
--
作者：
Cabrera-Salazar, M. A.;Bercury, S. D.;Scheule, R. K.
戈谢病是由葡萄糖脑苷酶缺陷引起的。因此，糖脂质葡萄糖神经酰胺（GluCer）和葡萄糖鞘氨酸（GluSph）的降解受损，随后它们的积累会导致严重的病理和早期死亡。1型戈谢病患者可以通过静脉注射替代酶成功治疗，但这种酶不能到达中枢神经系统，因此不能改善2型和3型戈谢病的神经系统受累。作为治疗这些后一种患者的一种潜在方法，我们在神经病变戈谢病小鼠模型中评估了重组人糖脑苷酶（rhGC）在脑室内（ICV）给药。ICV给药导致酶分布在整个大脑，减轻了该小鼠模型多个大脑区域的神经病理。治疗还导致血糖和血糖ph呈剂量依赖性下降，并显著延长了生存期。为了评估持续酶传递的潜力，一组动物用一种编码hGC的腺相关病毒载体治疗ICV，结果进一步延长了生存期。这些数据表明，ICV给药rhGC可能是2/3型戈谢病患者的一种潜在治疗方法。需要在大型动物中进行临床前评估，以确定该方法在临床中的可转译性。(C) 2010爱思唯尔公司版权所有。
Gaucher disease is caused by a deficit in the enzyme glucocerebrosidase. As a consequence, degradation of the glycolipids glucosylceramide (GluCer) and glucosylsphingosine (GluSph) is impaired, and their subsequent buildup can lead to significant pathology and early death. Type 1 Gaucher patients can be treated successfully with intravenous replacement enzyme, but this enzyme does not reach the CNS and thus does not ameliorate the neurological involvement in types 2 and 3 Gaucher disease. As one potential approach to treating these latter patients, we have evaluated intracerebroventricular (ICV) administration of recombinant human glucocerebrosidase (rhGC) in a mouse model of neuronopathic Gaucher disease. ICV administration resulted in enzyme distribution throughout the brain and alleviated neuropathology in multiple brain regions of this mouse model. Treatment also resulted in dose-dependent decreases in GluCer and GluSph and significantly extended survival. To evaluate the potential of continuous enzyme delivery, a group of animals was treated ICV with an adeno-associated viral vector encoding hGC and resulted in a further extension of survival. These data suggest that ICV administration of rhGC may represent a potential therapeutic approach for type 2/3 Gaucher patients. Preclinical evaluation in larger animals will be needed to ascertain the translatability of this approach to the clinic. (C) 2010 Elsevier Inc. All rights reserved.