CNS Penetration of Intrathecal-Lumbar Idursulfase in the Monkey, Dog and Mouse: Implications for Neurological Outcomes of Lysosomal Storage Disorder
CNS Penetration of Intrathecal-Lumbar Idursulfase in the Monkey, Dog and Mouse: Implications for Neurological Outcomes of Lysosomal Storage Disorder
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DOI：
10.1371/journal.pone.0030341
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发表时间：
2012-01-18
期刊：
影响因子：
3.7
通讯作者：
Heartlein, Michael W.
中科院分区：
文献类型：
--
作者：
Calias, Pericles;Papisov, Mikhail;Heartlein, Michael W.
治疗许多中枢神经系统（CNS）疾病的一个主要挑战是缺乏向大脑输送生物制剂的方便有效的方法。 II 型粘多糖贮积症（亨特综合征）是一种罕见的遗传性溶酶体贮积症，由艾杜糖醛酸 2-硫酸酯酶 (I2S) 缺乏所致。 I2S 是一种大型、高度糖基化的酶。静脉给药不太可能是治疗疾病相关神经系统结果的有效疗法，因为疾病相关的神经系统结果需要酶进入脑细胞，特别是神经元和少突胶质细胞。我们证明，在狗和非人灵长类动物中，脑室内和腰椎鞘内注射重组 I2S 会导致酶在脑实质中广泛分布，包括在神经元和少突胶质细胞的溶酶体中显着沉积。腰椎鞘内给药也导致酶递送至脊髓，而心室内给药后在那里检测到很少的酶。小鼠粘多糖贮积症 II 模型可用。对酶缺陷动物进行腰部注射重组 I2S 可以减少浅层和深层脑组织中糖胺聚糖的储存，同时形态也得到改善。观察到的酶从脑脊液到 CNS 组织的转运模式以及由此产生的生物活性 (a) 值得进一步研究通过腰椎导管鞘内递送 I2S 作为亨特综合征神经系统症状的实验性治疗方法；(b) 可能对生物制药的 CNS 治疗具有更广泛的影响。
A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.