AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation.
Xin WuYuanhuan YuMeiyan WangDi DaiJianli YinWenjing LiuDeqiang KongShasha TangMeiyao MengTian GaoYuanjin ZhangYang ZhouNingzi GuanShangang ZhaoHaifeng YePublished in: Nature communications (2024)
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.
Keyphrases
- gene therapy
- poor prognosis
- binding protein
- signaling pathway
- endothelial cells
- dna methylation
- gene expression
- copy number
- oxidative stress
- genome wide
- type diabetes
- chronic obstructive pulmonary disease
- pi k akt
- metabolic syndrome
- cell proliferation
- drug induced
- induced pluripotent stem cells
- metal organic framework
- cystic fibrosis
- insulin resistance
- simultaneous determination
- atopic dermatitis