IR@PKUHSC  > 北京大学第二临床医学院
学科主题临床医学
The enhancing effects of the light chain on heavy chain secretion in split delivery of factor VIII gene
Chen, Lingxia; Zhu, Fuxiang; Li, Juan; Lu, Hui; Jiang, Haiyan; Sarkar, Rita; Arruda, Valder R.; Wang, Jinhui; Zhao, Jennifer; Pierce, Glenn F.; Ding, Qiulan; Wang, Xuefeng; Wang, Hongli; Pipe, Steven W.; Liu, Xiang-Qin; Xiao, Xiao; Camire, Rodney M.; Xiao, Weidong
刊名MOLECULAR THERAPY
2007-10-01
DOI10.1038/sj.mt.6300268
15期:10页:1856-1862
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]HEMOPHILIA-A MICE ; HYDRODYNAMICS-BASED TRANSFECTION ; DNAB INTEIN ; VECTORS ; COAGULATION ; THERAPY ; PROTEIN ; EXPRESSION ; MUTATIONS ; ANIMALS
英文摘要

Coagulation factor VIII (FVIII) is secreted as a heterodimer consisting of a heavy chain (HC) and a light chain (LC), which can be expressed independently and reassociate with recovery of biological activity. Because of the size limitation of adeno-associated virus (AAV) vectors, a strategy for delivering the HC and LC separately has been developed. However, the FVIII HC is secreted 10-100-fold less efficiently than the LC. In this study, we demonstrated that the F309S mutation and enhanced B-domain glycosylations alone are not sufficient to improve FVIII HC secretion, which suggested a role of the FVIII LC in regulating HC secretion. To characterize this role of the FVIII LC, we compared FVIII HC secretion with and without the LC via post-translational protein trans-splicing. As demonstrated in vitro, ligation of the LC to the HC significantly increased HC secretion. Such HC secretion increases were also confirmed in vivo by hydrodynamic injection of FVIII intein plasmids into hemophilia A mice. Moreover, similar enhancement of HC secretion can also be observed when the LC is supplied in trans, which is probably due to the spontaneous association of the HC and the LC in the secretion pathway. In sum, enhancing the secretion of the FVIII HC polypeptide may require the proper association of the FVIII LC polypeptide in cis or in trans. These results may be helpful in designing new strategies to improve FVIII gene delivery.

语种英语
WOS记录号WOS:000249778000021
引用统计
被引频次:28[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/400002259/55955
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.Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
3.Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada
4.Univ N Carolina, Sch Pharm, Chapel Hill, NC USA
5.Bayer HealthCare Pharmaceut, Berkeley, CA USA
6.Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Shanghai 200030, Peoples R China
7.Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA
8.Peking Univ, Peoples Hosp, Beijing 100871, Peoples R China
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GB/T 7714
Chen, Lingxia,Zhu, Fuxiang,Li, Juan,et al. The enhancing effects of the light chain on heavy chain secretion in split delivery of factor VIII gene[J]. MOLECULAR THERAPY,2007,15(10):1856-1862.
APA Chen, Lingxia.,Zhu, Fuxiang.,Li, Juan.,Lu, Hui.,Jiang, Haiyan.,...&Xiao, Weidong.(2007).The enhancing effects of the light chain on heavy chain secretion in split delivery of factor VIII gene.MOLECULAR THERAPY,15(10),1856-1862.
MLA Chen, Lingxia,et al."The enhancing effects of the light chain on heavy chain secretion in split delivery of factor VIII gene".MOLECULAR THERAPY 15.10(2007):1856-1862.
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