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

Authors: Fan CH, Ting CY, Lin CY, Chan HL, Chang YC, Chen YY, Liu HL, Yeh CK

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To develop and evaluate a noninvasive, focused ultrasound-triggered cationic microbubble platform for targeted non-viral delivery of GDNF genes across the blood–brain barrier to treat Parkinson’s disease.

Disease model Parkinson's disease

Cargo name and characteristics GDNF gene (non-viral plasmid DNA encoding glial cell line-derived neurotrophic factor)

Route of administration systemic transvascular (intravenous)

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) combined with GDNF-plasmid-loaded cationic microbubbles restored GDNF and dopamine levels, protected/recovered tyrosine-hydroxylase–positive dopaminergic neurons and reversed motor deficits in 6-OHDA Parkinson’s disease rats. The authors found a 1-MHz FUS at 0.7 MPa to be effective and safe for BBB opening and gene delivery (1.0 MPa caused erythrocyte extravasation/damage).

Duration of biological effect 8 weeks

Safety-related matter Histological analysis (H&E) indicated that the selected FUS parameters (0.7 MPa) opened the BBB without erythrocyte extravasation or brain tissue damage and the authors state these parameters are safe; however, they report that higher FUS pressure (1.0 MPa) caused erythrocyte extravasation and caution that over-excitation of FUS, high MB doses, or larger MBs can risk intracerebral hemorrhage, brain tissue damage, and other neurological adverse effects.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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