IR@PKUHSC  > 北京大学第二临床医学院
学科主题临床医学
Enhanced Factor VIII Heavy Chain for Gene Therapy of Hemophilia A
Chen, Lingxia1,2; Lu, Hui1; Wang, Jinhui1; Sarkar, Rita1; Yang, Xiao1; Wang, Hongli3; High, Katherine A.1,4; Xiao, Weidong1
刊名MOLECULAR THERAPY
2009-03-01
DOI10.1038/mt.2008.292
17期:3页:417-424
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]RECOMBINANT ADENOASSOCIATED VIRUS ; COAGULATION-FACTOR VIII ; VON-WILLEBRAND-FACTOR ; FACTOR-IX ; LIGHT-CHAIN ; BLOOD-COAGULATION ; AAV VECTORS ; INTRAMUSCULAR INJECTION ; SUSTAINED EXPRESSION ; PACKAGING CAPACITY
英文摘要

Hemophilia A gene therapy using recombinant adenovirus-associated virus (AAV) vectors has been hampered by the size of the factor VIII (FVIII) cDNA. Previously, splitting the FVIII coding sequence into a heavy-chain (HC) fragment and a light-chain (LC) fragment for dual recombinant AAV vector delivery has been successfully explored. However, the main disadvantage of this approach is a "chain imbalance" problem in which LC secretion is similar to 1-2 logs higher than that of HC, and therefore, the majority of protein synthesized is nonfunctional. To improve HC secretion, we constructed alternate FVIII HCs based on our observation that LC facilitates HC secretion. To our surprise, most of the new HC molecules exhibited enhanced expression over the traditional HC molecule (HC(745)). The optimized HC mutein, HC(HL), including additional acidic-region-3 (ar3) sequences, exhibited three-to fivefold higher activity in both enzyme-linked immunosorbent assay (ELISA) and activated partial thromboplastin time (aPTT) assay in in vitro testing. Further characterization suggested ar3 sequences increased HC secretion, rather than promoting HC synthesis. Intravenous delivery of AAV8-HC(HL)+AAV8-LC or AAV8-HC(745)+AAV8-LC achieved phenotypic correction in hemophilia A mice. Mice receiving AAV8-HC(HL)+AAV8-LC achieved three-to fourfold higher HC expression than AAV8-HC(745)+AAV8-LC, consistent with the FVIII functional assays. HC(HL) should be substituted for HC(745) in a dual AAV vector strategy due to its enhanced expression.

语种英语
WOS记录号WOS:000263788200009
项目编号HL080789 ; HL084381
资助机构National Institutes of Health
引用统计
被引频次:21[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/400002259/57148
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, Peoples R China
3.Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Shanghai 200030, Peoples R China
4.Childrens Hosp Philadelphia, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
推荐引用方式
GB/T 7714
Chen, Lingxia,Lu, Hui,Wang, Jinhui,et al. Enhanced Factor VIII Heavy Chain for Gene Therapy of Hemophilia A[J]. MOLECULAR THERAPY,2009,17(3):417-424.
APA Chen, Lingxia.,Lu, Hui.,Wang, Jinhui.,Sarkar, Rita.,Yang, Xiao.,...&Xiao, Weidong.(2009).Enhanced Factor VIII Heavy Chain for Gene Therapy of Hemophilia A.MOLECULAR THERAPY,17(3),417-424.
MLA Chen, Lingxia,et al."Enhanced Factor VIII Heavy Chain for Gene Therapy of Hemophilia A".MOLECULAR THERAPY 17.3(2009):417-424.
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