Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

A preliminary study of Parkinson's gene therapy via sono-magnetic sensing gene vector for conquering extra/intracellular barriers in mice.

BACKGROUND: Non-virus genetic treatment for Parkinson's disease (PD) via plasmid glial cell-line derived neurotrophic factor (pGDNF) has shown potential for repairing damaged dopaminergic neurons. However, development of this gene therapy is largely hampered by the insufficient transfection efficiency as a result of the cell membrane, lysosome, and cytoskeleton meshwork. METHODS: In this study, we propose the use of polyethylenimine (PEI)-superparamagnetic iron oxide-plasmid DNA (pDNA)-loaded microbubbles (PSp-MBs) in conjunction with focused ultrasound (FUS) and two-step magnetic navigation to provide cavitation, proton sponge effect and magnetic effects to increase the efficiency of gene delivery. RESULTS: The gene transfection rate in the proposed system was 2.2-fold higher than that of the commercial agent (TransIT®-LT1). The transfection rate could be boosted ∼11%, ∼10%, and 6% by cavitation-magnetic hybrid enhanced cell membrane permeabilization, proton sponge effect, and magnetic-assisted cytoskeleton-reorganization, respectively. In vivo data suggested that effective gene delivery with this system results in a 3.2-fold increase in recovery of dopaminergic neurons and a 3.9-fold improvement in the motor behavior when compared to untreated genetic PD mice. CONCLUSIONS: We proposed that this novel FUS-magnetic hybrid gene delivery platform could be integrated with a variety of therapeutic genes for treating neurodegenerative diseases in the future.