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

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

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.