Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms
Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms
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DOI：
10.15252/emmm.201708730
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发表时间：
2018-07-01
影响因子：
11.1
通讯作者：
Bigger, Brian W.
中科院分区：
文献类型：
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作者：
Gleitz, Helene F. E.;Liao, Ai Yin;Bigger, Brian W.
儿童溶酶体贮积症粘多糖样沉积症II型是由IDS突变引起的，导致乙酰肝素和硫酸皮肤素蓄积，引起严重的神经变性、骨骼疾病和心肺疾病。大多数患者表现出认知症状，这不能用酶替代疗法治疗，因为天然IDS不能穿过血脑屏障。我们测试了一种脑靶向造血干细胞基因治疗方法，使用慢病毒IDS融合ApoEII（IDS.ApoEII）与慢病毒表达正常IDS或正常骨髓移植相比。在粘多糖样沉积症II型小鼠中，所有治疗均校正外周疾病，但仅IDSdApoEII介导脑病理学和行为的完全正常化，与IDS相比提供显著增强的校正。正常的骨髓移植没有实现大脑矫正。虽然校正了巨噬细胞向脑的运输，分泌IDS/IDS.ApoEII酶用于交叉校正，但IDS.ApoEII在血浆中的活性更高，并且通过硫酸乙酰肝素/ApoE依赖性受体和甘露糖-6-磷酸受体两者被摄取并跨脑内皮细胞转运显著优于IDS。脑靶向造血干细胞基因治疗为MPS II患者提供了一种有前途的治疗方法。
The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross-correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE-dependent receptors and mannose-6-phosphate receptors. Brain-targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients.