TY - JOUR
T1 - AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation
AU - Wu, Xin
AU - Yu, Yuanhuan
AU - Wang, Meiyan
AU - Dai, Di
AU - Yin, Jianli
AU - Liu, Wenjing
AU - Kong, Deqiang
AU - Tang, Shasha
AU - Meng, Meiyao
AU - Gao, Tian
AU - Zhang, Yuanjin
AU - Zhou, Yang
AU - Guan, Ningzi
AU - Zhao, Shangang
AU - Ye, Haifeng
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85184392919
UR - https://www.scopus.com/pages/publications/85184392919#tab=citedBy
U2 - 10.1038/s41467-024-45383-z
DO - 10.1038/s41467-024-45383-z
M3 - Article
C2 - 38321056
AN - SCOPUS:85184392919
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
ER -