title: Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson's Disease.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013 Taiwan.
authors.forename: Ching-Hsiang
authors.initials: CH
authors.lastname: Fan
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013 Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Ting
authors.affiliation: Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, 33302 Taiwan.
authors.forename: Chung-Yin
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013 Taiwan.
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Yuan-Chih
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Biomedical Engineering, National Yang Ming University, Taipei, 11221 Taiwan.
authors.forename: You-Yin
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, 33302 Taiwan.|Department of Electrical Engineering, Chang-Gung University, Taoyuan, 33302 Taiwan.
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013 Taiwan.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Yeh
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D045423:Microbubbles; D009043:Motor Activity; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D010539:Permeability; D010641:Phenotype; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D014162:Transfection; D000069453:Ultrasonic Waves
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor