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.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…This intervention has shown efficacy in delivering various compounds of different molecular weights into the brain parenchyma, including contrast agents, sugars, antibodies, chemotherapeutics, and neurotrophic factors . Aside from the direct delivery of the pharmacological agent, FUS‐facilitated viral and nonviral vector‐based gene delivery has been proven feasible to promote the long‐term expression of endogenous proteins …”

“…41 This intervention has shown efficacy in delivering various compounds of different molecular weights into the brain parenchyma, including contrast agents, 42 sugars, 43 antibodies, 44 chemotherapeutics, 45 and neurotrophic factors. 6,25,43,[46][47][48][49] Aside from the direct delivery of the pharmacological agent, FUS-facilitated viral and nonviral vector-based gene delivery has been proven feasible to promote the long-term expression of endogenous proteins. 6,46,49 An FUS-induced BBB opening is an innovative and noninvasive approach to achieve drug delivery within the CNS by providing significant advantages when compared with other approached in terms of targeting, noninvasiveness, and reversibility.…”

“…6,25,43,[46][47][48][49] Aside from the direct delivery of the pharmacological agent, FUS-facilitated viral and nonviral vector-based gene delivery has been proven feasible to promote the long-term expression of endogenous proteins. 6,46,49 An FUS-induced BBB opening is an innovative and noninvasive approach to achieve drug delivery within the CNS by providing significant advantages when compared with other approached in terms of targeting, noninvasiveness, and reversibility. The recent advances in technical optimization and preclinical validation support the immense potential of the intervention as the drug-delivery technique of choice in neurodegeneration models.…”

Treatment of Movement Disorders With Focused Ultrasound

“…The delivery of glial-derived growth factor (GDNF) and the related factor neurturin from the blood was improved in rodents with the use of this procedure 2,74. Gene therapy with GDNF has been successful in restoring dopamine metabolism and reversing motor abnormalities in a toxin-induced rat model of PD 3. In this study, a plasmid expressing GDNF was preloaded into the microbubbles to enhance its concentration in the region of pFUS-mediated BBB opening.…”

Focused ultrasound as an evolving therapy for Parkinson's disease

“…The workshop saw discussion and results from studies examining several forms of disease‐modifying therapeutics in PD and their enhanced delivery with FUS across the BBB. This work is reviewed in the article by Karakatsani and colleagues, which also includes several of the original researchers in this field …”