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

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

来源：Nature Communications, 2024, 15(1): 1122.

DOI：10.1038/s41467-024-45383-z

• GENE-THERAPY
• RECEPTOR
• LIVER
• EXPRESSION
• TRANSDUCTION
• EVOLUTION
• CIRCUITS
• VECTORS
• FAMILY
• MODEL

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 (Delta hFGF21 or Delta mIL-4). Our odorant-molecule-controlled system can advance gene-based precision therapies for human diseases. @@@ Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.

• 单位
  河北医科大学; Tongji university