期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 40, 期 6, 页码 1338-1350出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X19865917
关键词
AAV; endothelial cells; gene therapy; lysosomal storage disorder; Sandhoff disease
资金
- German Research Foundation (DFG) [SCHW416/9-1]
In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme beta-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, beta-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb(-/-) mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human beta-hexosaminidase subunit A and B (HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG-HEXA and AAV-BR1-CAG-HEXB transduced brain endothelial cells, which subsequently released beta-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.
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