Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; Department of Nephrology and Clinical Poison Center, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.
Department of Electrical Engineering, Chang Gung University, Taoyuan, 333, Taiwan.
Brain Stimul. 2019 Sep-Oct;12(5):1143-1150. doi: 10.1016/j.brs.2019.04.011. Epub 2019 Apr 27.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene encoding the huntingtin (Htt) protein, which results in a protein containing an abnormally expanded polyglutamine (polyQ) sequence. The expanded polyQ in the Htt protein is toxic to brain cells. No therapy exists to delay disease progression.
This study describes a gene-liposome system that synergistically applied focused ultrasound (FUS)-blood-brain barrier (BBB) opening for rescuing motor and neuropathological impairments when administered from pre to post-symptomatic transgenic mouse models of HD. DPPC liposomes (LPs) are designed to carry glia cell line-derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex. Pulsed FUS exposure with microbubbles (MBs) was used to induce BBB opening for non-viral, non-invasive, and targeted gene delivery into the central nervous system (CNS) for therapeutic purposes.
FUS-gene therapy significantly improved motor performance with GDNFp-LPs + FUS treated HD mice equilibrating longer periods in the animal behavior. Reflecting the improvements observed in motor function, GDNF overexpression results in significantly decreased formation of polyglutamine-expanded aggregates, reduced oxidative stress and apoptosis, promoted neurite outgrowth, and improved neuronal survival. Immunoblotting and histological staining further confirmed the neuroprotective effect from delivery of GDNF genes to neuronal cells.
This study suggests that the GDNFp-LPs plus FUS sonication can provide an effective gene therapy to achieve local extravasation and triggered gene delivery for non-invasive in vivo treatment of CNS diseases.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由编码亨廷顿蛋白（Htt）的基因中的 CAG 三核苷酸重复扩展引起，导致含有异常扩展的多聚谷氨酰胺（polyQ）序列的蛋白质。Htt 蛋白中的扩展 polyQ 对脑细胞有毒。目前尚无治疗方法可延缓疾病进展。
本研究描述了一种基因脂质体系统，该系统协同应用聚焦超声（FUS）-血脑屏障（BBB）开放，从转基因 HD 小鼠模型的前到后症状期给药，以挽救运动和神经病理学损伤。DPPC 脂质体（LPs）设计用于携带胶质细胞系衍生的神经营养因子（GDNF）质粒 DNA（GDNFp）以形成 GDNFp-脂质体（GDNFp-LPs）复合物。使用脉冲 FUS 暴露微泡（MBs）诱导 BBB 开放，用于非病毒、非侵入性和靶向基因递送至中枢神经系统（CNS）以进行治疗。
FUS-基因治疗显着改善了 GDNFp-LPs+FUS 治疗的 HD 小鼠的运动表现，使动物行为中的平衡时间更长。反映在运动功能的改善上，GDNF 过表达导致多聚谷氨酰胺扩展聚集物的形成减少、氧化应激和细胞凋亡减少、促进神经突生长和神经元存活增加。免疫印迹和组织学染色进一步证实了从神经元细胞递送达 GDNF 基因的神经保护作用。
本研究表明，GDNFp-LPs 加 FUS 超声可以提供有效的基因治疗，以实现局部渗出和触发基因传递，用于非侵入性体内治疗 CNS 疾病。
