腋臭严重影响患者身心健康，手术虽能够缓解患者异味，但副效应大。深入认识腋臭发病机制、探讨无创安全的治疗手段具有重要意义。课题组研究发现，在遗传和激素共同作用下，腋臭患者顶泌汗腺细胞载脂蛋白D（ApoD）表达异常增加，后者进一步引起(E)-3-甲基-2-己烯酸（E-3M2H）分泌增多，是腋臭发病的主要原因。因此，探索安全、高效、靶向降低ApoD表达的基因治疗策略有望从根本上减少E-3M2H的分泌达到治疗腋臭的目的。本项目拟利用已有构建条件性表达RNAi载体和合成低脱靶效应RNAi的研发基础，设计干涉ApoD的不同策略，并将它们分别制备成超声微泡；在此基础上，以汗腺结构与人极为相似的3岁龄恒河猴为研究对象，小动物高频超声引导下将上述超声微泡注入汗腺区，利用空泡效应将ApoD干涉序列靶向输送到汗腺细胞，观察不同RNAi策略对ApoD的靶向干涉效果及对腋臭的短期和长期疗效，为腋臭的治疗提供新的思路

Axillary osmidrosis is a benign disorder that causes functional and emotional problems in Asian patients. Recently surgery is the main therapy, which produces severe side-effects. Deciphering the underlying mechanism for the pathology of osmidrosis and exploring an alternative therapeutic strategy is of great value for osmidrosis. Previous studies by others and us have revealed that increased E-3M2H secretion is the leading cause of the disease, while enhancaed ApoD expression is responsible for the E-3M2H secretion. To this end, we hypothesize that targeted delivery of the siRNA against ApoD would be an alternative therapy for osmidrosis. In this study, we would construct siRNA against ApoD by the following different methods ①synthesize the traditional symmetric RNAi duplexes;② synthesize the asymmetric RNAi duplexes based on our newly designed methods; ③ shRNA driven by androgen receptor. These different RNAi strategies were used to knockdown the ApoD and the functional effects on E-3M2H secretion was examined by MS quantification in an in vitro cell model. We then incorporate the shRNA or RNAi duplex into the ultrasound microbubbles to deliver these siRNA specifically the sweat gland in the axillary region by ultrasound targeted microbubble destruction (UTMD) in the monkey model, which mimics the human axillary osmidrosis faithfully. The therapeutic effects and their duration of the UTMD based drug delivery would be examined through E-3M2H quantification and the side-effects would be examined by testing the off-target effects of siRNA and the local inflammation response. Our study here would further the understanding of the pathology of axillary osmidrosis, and also provides an alternative therapeutic strategy.