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 and Haifeng Ye ()
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Xin Wu: East China Normal University
Yuanhuan Yu: East China Normal University
Meiyan Wang: East China Normal University
Di Dai: East China Normal University
Jianli Yin: East China Normal University
Wenjing Liu: East China Normal University
Deqiang Kong: East China Normal University
Shasha Tang: Tongji University
Meiyao Meng: East China Normal University
Tian Gao: East China Normal University
Yuanjin Zhang: East China Normal University
Yang Zhou: East China Normal University
Ningzi Guan: East China Normal University
Shangang Zhao: University of Texas Health Science Center at San Antonio
Haifeng Ye: East China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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 (AAVMUSE) based on a G protein-coupled murine olfactory receptor (MOR215-1) and a synthetic cAMP-responsive promoter (PCRE). Upon exposure to the trigger, muscone binds to MOR215-1 and activates the cAMP signaling pathway to initiate transgene expression. AAVMUSE 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 AAVMUSE to treat two chronic inflammatory diseases: nonalcoholic fatty liver disease (NAFLD) and allergic asthma, showing that inhalation of muscone—after only one injection of AAVMUSE—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.

Date: 2024
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DOI: 10.1038/s41467-024-45383-z

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