Half-Life Extension Enhances Drug Efficacy in Adeno-Associated Virus Delivered Gene Therapy
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
Affiliations
Huifang Wu
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
Dan Hu
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
Quanxiao Li
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
Chunyu Wang
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
Xiaoyi Zhu
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
Wei Li
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
Binfan Chen
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
Ping Ji
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
Keke Huang
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
Ailing Huang
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
Jinghe Huang
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
Dimiter S. Dimitrov
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
Yanling Wu
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; Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 200032, China; Corresponding authors.
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; Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 200032, China; Corresponding authors.
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.
