AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation

Xin Wu; Yuanhuan Yu; Meiyan Wang; Di Dai; Jianli Yin; Wenjing Liu; Deqiang Kong; Shasha Tang; Meiyao Meng; Tian Gao; Yuanjin Zhang; Yang Zhou; Ningzi Guan; Shangang Zhao; Haifeng Ye

doi:10.1038/s41467-024-45383-z

AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation

Nat Commun. 2024 Feb 6;15(1):1122. doi: 10.1038/s41467-024-45383-z.

Authors

Xin Wu^#^{1

2}, Yuanhuan Yu^#¹, Meiyan Wang^#^{1

3}, Di Dai¹, Jianli Yin^{1

3}, Wenjing Liu¹, Deqiang Kong¹, Shasha Tang⁴, Meiyao Meng¹, Tian Gao¹, Yuanjin Zhang¹, Yang Zhou^{1

5}, Ningzi Guan¹, Shangang Zhao⁶, Haifeng Ye^{7

8

9}

Affiliations

¹ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China.
² Institute of Medical Technology, Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China.
³ Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China.
⁴ Department of Breast Surgery, Tongji Hospital, School of Medicine, Tongji University, Xincun Road 389, Shanghai, 200065, China.
⁵ Wuhu Hospital, Health Science Center, East China Normal University, Middle Jiuhua Road 263, Wuhu, Anhui, China.
⁶ Division of Endocrinology, Department of Medicine, Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
⁷ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China. hfye@bio.ecnu.edu.cn.
⁸ Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China. hfye@bio.ecnu.edu.cn.
⁹ Wuhu Hospital, Health Science Center, East China Normal University, Middle Jiuhua Road 263, Wuhu, Anhui, China. hfye@bio.ecnu.edu.cn.

^# Contributed equally.

Abstract

Gene therapies provide treatment options for many diseases, but the safe and long-term control of therapeutic transgene expression remains a primary issue for clinical applications. Here, we develop a muscone-induced transgene system packaged into adeno-associated virus (AAV) vectors (AAV_MUSE) based on a G protein-coupled murine olfactory receptor (MOR215-1) and a synthetic cAMP-responsive promoter (P_CRE). Upon exposure to the trigger, muscone binds to MOR215-1 and activates the cAMP signaling pathway to initiate transgene expression. AAV_MUSE enables remote, muscone dose- and exposure-time-dependent control of luciferase expression in the livers or lungs of mice for at least 20 weeks. Moreover, we apply this AAV_MUSE to treat two chronic inflammatory diseases: nonalcoholic fatty liver disease (NAFLD) and allergic asthma, showing that inhalation of muscone-after only one injection of AAV_MUSE-can achieve long-term controllable expression of therapeutic proteins (ΔhFGF21 or ΔmIL-4). Our odorant-molecule-controlled system can advance gene-based precision therapies for human diseases.

MeSH terms

Alprostadil* / metabolism
Animals
Cycloparaffins* / metabolism
Dependovirus / genetics
Genetic Vectors
Humans
Mice
Odorants
Receptors, G-Protein-Coupled / metabolism
Transgenes

Substances

muscone
Alprostadil
Cycloparaffins
Receptors, G-Protein-Coupled

Abstract

MeSH terms

Substances

Grants and funding