延长腺相关病毒递送药物的半衰期提高治疗效果  

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

作　　者：吴会芳 胡丹 李泉晓 王春雨 朱晓艺 李威 陈宾凡 季萍 黄可可 黄爱玲 黄竞荷 Dimiter S.Dimitrov 吴艳玲 应天雷 Huifang Wu;Dan Hu;Quanxiao Li;Chunyu Wang;Xiaoyi Zhu;Wei Li;Binfan Chen;Ping Ji;Keke Huang;Ailing Huang;Jinghe Huang;Dimiter S.Dimitrov;Yanling Wu;Tianlei Ying(MOE/NHC Key Laboratory of Medical Molecular Virology,Shanghai Institute of Infectious Disease and Biosecurity&School of Basic Medical Sciences,Fudan University,Shanghai 200032,China;Department of Medicine,University of Pittsburgh,Pittsburgh,PA 15261,USA;Shanghai Engineering Research Center for Synthetic Immunology,Shanghai 200032,China)

机构地区：[1]MOE/NHC Key Laboratory of Medical Molecular Virology,Shanghai Institute of Infectious Disease and Biosecurity&School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [2]Department of Medicine,University of Pittsburgh,Pittsburgh,PA 15261,USA [3]Shanghai Engineering Research Center for Synthetic Immunology,Shanghai 200032,China

出　　处：《Engineering》2023年第2期203-213,M0008,共12页工程（英文）

基　　金：supported by the National Key Research and Development Program of China(2019YFA0904400);the National Natural Science Foundation of China(81822027,81630090,and 81902108)。

摘　　要：延长基于蛋白质治疗药物的半衰期可以提高药物疗效。然而,基因治疗本质上是长期表达所需的治疗性药物,药物半衰期对基因治疗疗效的影响尚不清楚。在这项腺相关病毒(adeno-associated virus,AAV)基因治疗研究中,通过与免疫球蛋白G1(immunoglobulin G 1,IgG1)可溶性单体Fc区(soluble monomeric IgG1 fragment crystallizable,sFc)或Fc区融合,设计了几种能够延长半衰期的蛋白质。研究表明,延长AAV递送的小分子双功能蛋白和成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)的半衰期显著增加了它们在血液循环中的浓度。此外,AAV递送FGF21延长其半衰期使2型糖尿病动物模型中肝损伤和血糖显著降低,并改善了葡萄糖耐量和胰岛素敏感性。这些结果证明了延长药物半衰期的基因治疗在应对人类疾病中的治疗潜力。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 demonstrate the therapeutic potential of gene therapy with prolonged drug half-life in the treatment of human diseases.

关 键 词：药物半衰期 葡萄糖耐量 腺相关病毒 免疫球蛋白G 血液循环 人类疾病 基因治疗 治疗性药物 

分 类 号：R96[医药卫生—药理学]