Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.
Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.
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DOI：
10.1038/mt.2015.189
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Haskins ME
中科院分区：
文献类型：
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作者：
Gurda BL;De Guilhem De Lataillade A;Bell P;Zhu Y;Yu H;Wang P;Bagel J;Vite CH;Sikora T;Hinderer C;Calcedo R;Yox AD;Steet RA;Ruane T;O'Donnell P;Gao G;Wilson JM;Casal M;Ponder KP;Haskins ME
粘多糖沉积症VII（MPS VII）是一种由β-D-葡萄糖醛酸酶（GUSB）突变引起的溶酶体贮积病，可导致糖胺聚糖（GAG）蓄积和多种临床表现，包括神经系统疾病。在此，将MPS VII犬静脉内（i. v.）和/或鞘内（i.t.）通过小脑延髓池与携带犬GUSB cDNA的AAV 9或AAVrh 10载体连接。尽管在3日龄时单独静脉注射导致正常的脑脊液（CSF）GUSB活性，但脑组织匀浆仅具有约1至6%的正常GUSB活性，并且继续具有升高的GAG储存。相比之下，i. t.与未处理的狗相比，在3周龄时注射导致CSF GUSB活性为正常的44倍，而脑组织匀浆具有>100%的正常GUSB活性和减少的GAG。在i.t.中消除了二次储存和炎症的标记物。给药犬和静脉注射减少-与未处理的狗相比。因为信息技术-与静脉内治疗的狗相比，治疗的狗在CNS组织中表达更高水平的GUSB，我们得出结论，i.t.在MPS VII的大型动物模型中，注射AAV 9或AAVrhlO载体比单独静脉内注射更有效。
Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.