Investigation of Focused Ultrasound-Targeted Emulsion Liposome-Encapsulated Therapeutic Plasmid Nanoparticles as a Novel Gene Therapy for Huntington’S Disease

Huntington’s disease (HD) is a devastating neurodegenerative disease that is caused by mutant huntingtin attacking neurons mainly in the basal ganglia, which are responsible for movements and intellectual faculties. 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 movements and in other symptoms, despite several symptoms-ameliorative treatment options. Fortunately recent extensive studies have shown that gene therapy provides an 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 pulsed focused ultrasound (FUS) sonicating can temporally and locally disrupt BBB and enhance the vascular permeability, resulting in increased delivery of drugs/genes across the BBB. The aim of the present study is to develop a novel and an effective non-viral system of emulsion liposomes composed of a perfluoropentane nanodroplet within the aqueous interior of a DPPC (dipalmitoylphosphatidylcholine) liposome, along with the therapeutic reporter genes brain-derived neurotrophic factor (BDNF) plasmid DNA (BpDNA) and, for the first time, demonstrate the advantages of both ultrasonic wave targeting and physical deposition of BpDNA directly inside cells in vivo, and hence determine whether or not a nanocarrier can be effectively delivered to brains through FUS-induced BBB opening. As the protective role of increased BpDNA in brain of HD is evident, the goal of the following studies is to investigate the therapeutic potential of enhancing BDNF expression in striatum of HD mice achieved by emulsion liposome-encapsulated BpDNA for HD prevention or treatment. The Specific Aims of this project are: Aim 1: to investigate if the mutant Htt can be efficiently expressed in neuronal-like Neuro2a cells to generate a HD cellular model and if lead BDNF plasmid can be efficiently expressed to rescue the cellular phenotype by using ultrasound sonication. Aim 2: to determine FUS systems enhancing BDNF expression and safety with in vivo image-guided systems and to demonstrate the capability of the designed system capable of targeted opening the BBB by using emulsion liposome-encapsulated BDNF plasmids (eLBpDNA) in HD transgenic mice, and successfully inducing gene transduction into targeted HD CNS tissues. Aim 3: to investigate the protective effect of lead BDNF overexpression on HD transgenic mice via FUS-targeted eLBpDNA system

Project ID:PB10507-2936
External Project ID:MOST105-2221-E182-008