MRI引导下聚焦超声联合PEG化脂质体-微泡复合物介导GDNF基因治疗帕金森病的实验研究

Parkinson's disease (PD), as a common neurodegenerative disorder, deserves attention because of lacking efficient therapy. Blood-brain barrier (BBB) preserves brain homeostasis and in the meanwhile has become an insurmountable barrier for the most drugs and genes into the brain, thus prohibits the development of gene therapy for PD. The MRI-guided focused ultrasound microbubbles (MBs) are competent for opening BBB noninvasively and locally to achieve targeted therapy for the central nervous system diseases intravenously, but the MBs have low drug-loading capacity. The PEGylated liposomes have high loading efficiency, but can't cross BBB and target a specific area. We intend to conjugate the therapeutic gene-loaded PEGylated liposomes to the MB surface through biotin-avidin linkage and develop an liposome-MB complex, which is able to effectively overcome the shortcomings of both and to achieve targeted delivery of gene into brain. As far as we know, this technique has not been reported in PD. In addition, GDNF possesses specific dopaminotrophic effects that are both neuroprotective and neuroregenerative, thus can be used as an ideal target for PD therapy. The present study aims to deliver GDNF gene-loaded PEG liposomes into the corpus striatum of PD rats by MRI-guided focused ultrasound MBs, so as to explore the effect of opening BBB of the method, and to confirm the therapeutic efficacy of GDNF overexpression in PD.

帕金森病(PD)作为一种常见的神经变性病，因缺少有效的治疗方法而备受关注，而血脑屏障(BBB)在维护脑稳态的同时也成为PD基因治疗的屏障。MRI引导下低频聚焦超声联合载基因或药物的微泡可无创、可逆、局部性地开放BBB，但微泡载基因能力低；PEG化脂质体具有较高的装载效率，但缺乏靶向性及跨BBB的能力。将PEG化脂质体结合到微泡表面，形成负载治疗基因的脂质体-微泡复合物，有效克服两者的不足，实现经静脉跨BBB的脑内靶向基因递送和转染。据我们所知，该项技术尚未在PD中应用。另外，GDNF对多巴胺能神经元具有特异性营养活性，可作为PD治疗的理想靶点。该研究将首次探讨MRI引导下低频聚焦超声联合微泡开放PD大鼠纹状体区的BBB，并利用PEG化脂质体-微泡复合物将负载的GDNF基因靶向递送至纹状体区，实现对PD的治疗作用，以寻找能突破BBB治疗PD的高效、安全的新方法。

帕金森病(PD)作为一种常见的神经变性病，因缺少有效的治疗方法而备受关注，而血脑屏障(BBB)在维护脑稳态的同时也成为PD基因治疗的屏障。MRI引导下低频聚焦超声联合载基因或药物的微泡可无创、可逆、局部性地开放BBB，但微泡载基因能力低；PEG化脂质体具有较高的装载效率，但缺乏靶向性及跨BBB的能力。将PEG化脂质体结合到微泡表面，形成负载治疗基因的脂质体-微泡复合物，有效克服两者的不足，实现经静脉跨BBB的脑内靶向基因递送和转染。同时我们将胶质细胞源性神经营养因子（glial cell line-derived neurotrophic factor,GDNF）和核受体Nurr1负载到脂质体-微泡复合物中，结果发现，脂质体-微泡复合物将负载的pGDNF 质粒和pNurr1质粒靶向递送到 PD 大鼠纹状体区，改善了PD大鼠的神经损伤和运动障碍。该研究首次探讨了MRI引导下低频聚焦超声联合微泡开放PD大鼠纹状体区的BBB，并利用PEG化脂质体-微泡复合物将负载的GDNF基因和Nurr1基因靶向递送至纹状体区，实现对PD的治疗作用，以寻找能突破BBB治疗PD的高效、安全的新方法。