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《工程(英文)》 >> 2023年 第21卷 第2期 doi: 10.1016/j.eng.2022.02.009

延长腺相关病毒递送药物的半衰期提高治疗效果

a 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
b Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States
c Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 200032, China

收稿日期: 2021-10-01 修回日期: 2022-02-06 录用日期: 2022-02-20 发布日期: 2022-03-22

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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,基因治疗本质上是提供了长期表达所需的治疗性蛋白,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。

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