2. Academic Validation
  3. AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation

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.
Xin Wu # 1 2,  Yuanhuan Yu # 1,  Meiyan Wang # 1 3,  Di Dai 1,  Jianli Yin 1 3,  Wenjing Liu 1,  Deqiang Kong 1,  Shasha Tang 4,  Meiyao Meng 1,  Tian Gao 1,  Yuanjin Zhang 1,  Yang Zhou 1 5,  Ningzi Guan 1,  Shangang Zhao 6,  Haifeng Ye 7 8 9
Affiliations

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.
PMID: 38321056 DOI: 10.1038/s41467-024-45383-z
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.

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