Fan Ching-Hsiang, Ting Chien-Yu, Lin Chung-Yin, Chan Hong-Lin, Chang Yuan-Chih, Chen You-Yin, Liu Hao-Li, Yeh Chih-Kuang
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013 Taiwan.
Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, 33302 Taiwan.
Sci Rep. 2016 Jan 20;6:19579. doi: 10.1038/srep19579.
Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson's disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.
胶质细胞源性神经营养因子（GDNF）可支持多巴胺能神经元的生长和存活。目前，中枢神经系统基因递送依赖于侵入性脑内注射以穿过血脑屏障。通过系统性经血管途径进行的非病毒基因递送是一种有吸引力的替代方法，因为它是非侵入性的，但仍缺乏高产率且靶向基因表达的方法。在本研究中，我们提出了一种新型的非病毒基因递送方法以实现靶向基因转染。开发了阳离子微泡作为基因载体，以实现气泡 - GDNF基因复合物的稳定形成，并且经颅聚焦超声（FUS）暴露与气泡 - 基因复合物同时相互作用可实现瞬时基因渗透并诱导局部GDNF表达。我们证明，聚焦超声触发的负载GDNFp的阳离子微泡平台可通过非侵入性给药途径实现非病毒靶向基因递送，在高滴度GDNF基因的靶向GDNF递送方面优于脑内注射，并且在帕金森病（PD）动物模型中具有神经保护作用，能够成功阻断PD综合征进展并恢复行为功能。本研究探索了使用FUS和气泡 - 基因复合物实现非侵入性和靶向基因递送以治疗神经退行性疾病的潜力。
