PMID- 30122074 OWN - NLM STAT- MEDLINE DCOM- 20200312 LR - 20200312 IS - 1557-7422 (Electronic) IS - 1043-0342 (Linking) VI - 30 IP - 2 DP - 2019 Feb TI - Delivery of Glucosylceramidase Beta Gene Using AAV9 Vector Therapy as a Treatment Strategy in Mouse Models of Gaucher Disease. PG - 155-167 LID - 10.1089/hum.2018.072 [doi] AB - Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene. Enzyme replacement treatment is the most effective therapy available for type 1 GD patients, but it is very expensive and does not improve neurologic outcomes in type 2 and 3 GD patients. This study evaluated the effectiveness of an adeno-associated virus 9 (AAV9) vector expressing the Gba gene delivered systemically in GD mouse models. To detect the therapeutic effects of the AAV9-mediated Gba transfer on the systemic symptoms of GD, an inducible whole-body Gba knockout mouse was developed in which tamoxifen effectively induced whole-body Gba gene deletion, and the mice displayed systemic symptoms of GD. The AAV9-CMV-Gba vector, with the expression of Gba driven by the universal CMV promoter, restored GCase activity in multiple organs and prolonged the lifespan in tamoxifen-induced GD mice after intravenous injection. Mice with brain-specific Gba deletion were also included in this study as a model of neuropathic GD (nGD) and injected intraperitoneally on postnatal day 5 with the AAV9-SYN-Gba vector; this improved the GCase activity, ameliorated the neuropathological changes and extended the mean lifespan two-fold. This study demonstrates that AAV9-mediated gene transfer is a potentially effective treatment for GD. FAU - Du, Sichen AU - Du S AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Ou, Huayuan AU - Ou H AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Cui, Renjie AU - Cui R AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Jiang, Nan AU - Jiang N AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Zhang, Meiqin AU - Zhang M AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Li, Xiaorong AU - Li X AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Ma, Jing AU - Ma J AD - 2 Children's Hospital, Fudan University, Shanghai, China. FAU - Zhang, Jin AU - Zhang J AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. FAU - Ma, Duan AU - Ma D AD - 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai China. AD - 2 Children's Hospital, Fudan University, Shanghai, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181016 PL - United States TA - Hum Gene Ther JT - Human gene therapy JID - 9008950 RN - EC 3.2.1.45 (Glucosylceramidase) SB - IM MH - Animals MH - *Dependovirus MH - Disease Models, Animal MH - *Gaucher Disease/enzymology/genetics/pathology/therapy MH - *Genetic Therapy MH - *Genetic Vectors MH - *Glucosylceramidase/biosynthesis/genetics MH - Mice MH - Mice, Knockout MH - *Transduction, Genetic OTO - NOTNLM OT - AAV9 OT - GD mouse model OT - Gaucher disease OT - gene therapy EDAT- 2018/08/21 06:00 MHDA- 2020/03/13 06:00 CRDT- 2018/08/21 06:00 PHST- 2018/08/21 06:00 [pubmed] PHST- 2020/03/13 06:00 [medline] PHST- 2018/08/21 06:00 [entrez] AID - 10.1089/hum.2018.072 [doi] PST - ppublish SO - Hum Gene Ther. 2019 Feb;30(2):155-167. doi: 10.1089/hum.2018.072. Epub 2018 Oct 16.