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学科主题临床医学
Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette
Lu, Hui1,2; Chen, Lingxia1,2,3; Wang, Jinhui1,2; Huack, Bernd1,2; Sarkar, Rita1,2; Zhou, Shangzhen1,2; Xu, Ray4; Ding, Qiulan5; Wang, Xuefeng5; Wang, Hongli5; Xiao, Weidong1,2
刊名HUMAN GENE THERAPY
2008-06-01
DOI10.1089/hum.2007.0182
19期:6页:648-654
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biotechnology & Applied Microbiology ; Genetics & Heredity ; Medicine, Research & Experimental
研究领域[WOS]Biotechnology & Applied Microbiology ; Genetics & Heredity ; Research & Experimental Medicine
关键词[WOS]PACKAGING CAPACITY ; GENE-THERAPY ; FACTOR-VIII ; VIRUS ; SECRETION ; HEAVY ; FVIII ; MICE
英文摘要

Hemophilia A is caused by a deficiency in the factor VIII (FVIII) gene. Constrained by limited packaging capacity, even the 4.3-kb B domain-deleted FVIII remained a challenge for delivery by a single adeno-associated viral (AAV) vector. Studies have shown that up to a 6.6-kb vector sequence may be packaged into AAV virions, which suggested an alternative strategy for hemophilia A gene therapy. To explore the usefulness of AAV vectors carrying an oversized FVIII gene, we constructed the AAV-FVIII vector under the control of a P-actin promoter with a cytomegalovirus enhancer (CB) and a bovine growth hormone (bGH) poly(A) sequence. The CB promoter plus bGH signal was shown to be 3- to 5-fold more potent than the mini-transthyretin (TTR) promoter with a synthetic poly(A) sequence for directing FVIII expression in the liver. Despite the 5.75-kb genome size of pAAV-CB-FVIII, sufficient AAV vectors were produced for in vivo testing. Approximately 3- to 5-fold more FVIII secretion was observed in animals receiving AAV-CB-FVIII vectors than in those receiving Standard-sized AAV-TTR-FVIII vectors. Both the activated partial thromboplastin time assay and the whole blood thromboelastographic analysis confirmed that AAV-FVIII vectors fully corrected the bleeding phenotype of hemophilia mice. These results suggest that AAV vectors with an oversized genome should be useful for not only hemophilia A gene therapy but also other diseases with large cDNA such as muscular dystrophy and cystic fibrosis.

语种英语
WOS记录号WOS:000257269800009
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被引频次:31[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/64812
专题北京大学第二临床医学院
作者单位1.Univ Penn, Med Ctr, Dept Pediat, Philadelphia, PA 19104 USA
2.Peking Univ, Peoples Hosp, Beijing 100044, Peoples R China
3.Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
4.Huaqiao Univ, Inst Mol Med, Quanzhou 362021, Fujian Province, Peoples R China
5.Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Shanghai 200025, Peoples R China
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Lu, Hui,Chen, Lingxia,Wang, Jinhui,et al. Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette[J]. HUMAN GENE THERAPY,2008,19(6):648-654.
APA Lu, Hui.,Chen, Lingxia.,Wang, Jinhui.,Huack, Bernd.,Sarkar, Rita.,...&Xiao, Weidong.(2008).Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette.HUMAN GENE THERAPY,19(6),648-654.
MLA Lu, Hui,et al."Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette".HUMAN GENE THERAPY 19.6(2008):648-654.
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