Focused Ultrasound-Induced Blood-Brain Barrier Opening for Gene Transfection and Expression in Huntington's Disease Mouse Model

Huntington’s disease (HD) is a genetically neurodegenerative disease with followed loss of mood changes, depression, irritability, or even declined in coordination and an unsteady gait. To date there is no proven method to prevent or to slow neurodegenerative disease progression. As the condition progresses, patients gradual worsen in controlling their movement and in other such symptoms, despite several treatment options such as pharmacologic therapy and/or surgery. Fortunately recent extensive studies have shown that gene therapy provides and attractive promise of improved control and enhanced treatment of such incurable diseases. However, blood-brain barrier (BBB) is the major drawback encountered for effectively delivering drugs/genes to the brain. Research studies have demonstrated that focused ultrasound (FUS) sonicating with microbubbles (MBs, average diameter: 2-3 m) can temporally and locally disrupt BBB and enhance the vascular permeability. The interaction of ultrasound wave with MBs in the brain vasculature can produce bubble’s oscillation, cavitation and microstreaming. Those activities might result in the temporal change of endothelial and vascular permeability. The aim of the present study is to develop an effective non-viral system of liposomes containing plasmid DNA (LpDNA) and, for the first time, demonstrate the advantages of both ultrasonic wave targeting and physical deposition of LpDNA directly inside cells in vivo, and hence demonstrate an increased transgenic expression. A functionalized liposome containing luciferase pLuc-N3 DNA encoded GDNF plasmid was used to determine whether or not a nanocarrier has been effectively delivered to brains through FUS-induced BBB opening. The approach of using LpDNA in combination with in vivo imaging system (IVIS) would make it possible to obtain semi-quantitative bioluminescent imaging evidence regarding the transgene expression of luciferase in brains. A safe operation procedure will be established by using this novel transgenic DNA delivery system combined a MRI image guiding system to handle the BBB opening. As the protective role of increased Luciferase/GDNF plasmid in HD is evident, the following studies to demonstrate liposome-encapsulated GDNF (Gial cell line-derived neurotrophic factor)/Luciferase for enhancing GDNF expression and investigate the therapeutic potentials for HD prevention or treatment. The proposed study may provide new prospects for HD therapeutics.

Project ID:PB10406-1300
External Project ID:MOST104-2218-E182-003