Noninvasive, Targeted and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease

• Published in: Scientific reports Vol. 6; no. 1; p. 19579
• Main Authors: Fan, Ching-Hsiang, Ting, Chien-Yu, Lin, Chung‐Yin, Chan, Hong-Lin, Chang, Yuan-Chih, Chen, You-Yin, Liu, Hao-Li, Yeh, Chih-Kuang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2016; Nature Publishing Group
• Subjects: 639/301/54/152; 692/308/2056; 692/4017; Animal diseases; Animal models; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Cell Line; Central nervous system; Disease Models, Animal; Dopamine receptors; Gene Expression; Gene transfer; Gene Transfer Techniques; Genetic Therapy; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - genetics; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Humanities and Social Sciences; Injection; Microbubbles; Motor Activity; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neuronal-glial interactions; Neuroprotection; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson's disease; Permeability; Phenotype; Plasmids - administration & dosage; Plasmids - genetics; Plasmids - metabolism; Rats; Recovery of function; Science; Transfection; Ultrasonic imaging; Ultrasonic Waves; Ultrasound
• ISSN: 2045-2322; 2045-2322
• 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.