Half-Life Extension Enhances Drug Efficacy in Adeno-Associated Virus Delivered Gene Therapy

被引:2
作者
Wu, Huifang [1 ,2 ]
Hu, Dan [1 ,2 ]
Li, Quanxiao [1 ,2 ]
Wang, Chunyu [1 ,2 ]
Zhu, Xiaoyi [1 ,2 ]
Li, Wei [3 ]
Chen, Binfan [1 ,2 ]
Ji, Ping [1 ,2 ]
Huang, Keke [1 ,2 ]
Huang, Ailing [1 ,2 ]
Huang, Jinghe [1 ,2 ]
Dimitrov, Dimiter S. [3 ]
Wu, Yanling [1 ,2 ,4 ]
Ying, Tianlei [1 ,2 ,4 ]
机构
[1] Fudan Univ, Shanghai Inst Infect Dis & Biosecur, MOE NHC Key Lab Med Mol Virol, Shanghai 200032, Peoples R China
[2] Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
[3] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA
[4] Shanghai Engn Res Ctr Synthet Immunol, Shanghai 200032, Peoples R China
来源
ENGINEERING | 2023年 / 21卷
基金
中国国家自然科学基金;
关键词
Gene therapy; Adeno-associated virus; Half-life; Fibroblast growth factor 21; Type 2 diabetes mellitus; FC FUSION PROTEIN; VIRAL VECTORS; POTENT; CD4;
D O I
10.1016/j.eng.2022.02.009
中图分类号
T [工业技术];
学科分类号
08 ;
摘要
Prolonged half-life of protein-based therapeutics can improve drug efficacy. However, the impact of drug half-life on gene therapy, which inherently provides long-lasting production of the desired therapeutic protein, remains unclear. In this study, several proteins with extended half-lives were engineered by fusion with the soluble monomeric immunoglobulin G 1 (IgG1) fragment crystallizable (sFc) or Fc region of IgG in adeno-associated virus (AAV)-delivered gene therapy. It was demonstrated that extending the half-life of a small-sized bifunctional protein and fibroblast growth factor 21 (FGF21) significantly increased their concentrations in the bloodstream circulation. Moreover, the half-life extension of AAV-delivered FGF21 resulted in a remarkable reduction in liver injury and blood glucose, and improved glucose tolerance and insulin sensitivity in type 2 diabetes mellitus animal models. These results demon-strate the therapeutic potential of gene therapy with prolonged drug half-life in the treatment of human diseases.(c) 2022 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
引用
收藏
页码:203 / 213
页数:11
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