Nini Phan

Background: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of misfolded α-synuclein protein in Lewy bodies.¹ PD is a progressively debilitating condition, marked by the cardinal symptoms of bradykinesia, resting tremor, and rigidity.¹ Current treatments, such as dopamine replacement therapy and deep brain stimulation, target symptom management but do not halt disease progression.² Projected to affect over 25 million individuals globally by 2050, there is an urgent need for disease-modifying therapies that address the underlying pathology.³ The blood-brain barrier (BBB), while protective, presents a critical obstacle for the delivery of therapeutic agents.^{4, 5} Recent studies have highlighted the use of MRI-guided low-intensity focused ultrasound (Li-FUS) as a noninvasive technique to transiently and precisely open the BBB, enabling targeted delivery of gene therapies and neuroprotective agents.^{5, 6, 7, 8}

Objective: This literature review aims to evaluate the emerging application of focused ultrasound for targeted gene and drug delivery across the BBB in Parkinson’s disease, with a focus on its potential for disease modification through gene silencing and neuroprotection.

Search Methods: An online search was conducted between 2017 and 2025 using PubMed and Google Scholar. Search terms included “focused ultrasound”, “Parkinson’s disease”, “blood-brain barrier”, “gene therapy”, “α-synuclein”, and “GDNF”.

Results: Preclinical studies demonstrated that Li-FUS combined with microbubbles allows for safe, region-specific BBB opening.^{5, 6, 7} This facilitates the delivery of therapeutic vectors such as AAV9 carrying short hairpin RNA (shRNA) to silence α-synuclein expression.⁶ In transgenic PD mouse models, gene silencing led to over 50% reduction in α-synuclein levels in affected regions like the SNpc, hippocampus, and olfactory bulb, with preserved neuronal integrity and no significant neurotoxicity.⁶ Additional studies using FUS to deliver glial cell line-derived neurotrophic factor (GDNF) nanoparticles showed a 2.8-fold increase in dopamine levels and enhanced motor function in PD rat models.^{5, 7} Molecular investigations revealed FUS-induced BBB modulation involves P₂X₇ receptor activation and tight junction protein downregulation (such as claudin-5 and occludin), enabling transient barrier disruption.⁴ Non-human primate and early-phase human clinical trials confirmed safe and targeted BBB opening with significant uptake of PET tracers in key brain regions.⁸ However, the presence of neutralizing antibodies (NAbs) against AAV vectors remains a major translational hurdle, potentially impairing gene delivery efficiency.⁸

Conclusions: Focused ultrasound represents a promising, noninvasive platform for delivering disease-modifying therapies in Parkinson’s disease. By enabling safe and targeted BBB disruption, FUS facilitates direct access of therapeutic vectors and neuroprotective agents to affected brain regions. This approach may shift the PD treatment approach from symptomatic relief to disease modification. Future studies must address challenges such as immune responses to viral vectors, long-term safety, and optimization of delivery protocols. Overall, Li-FUS holds significant potential to advance precision neuromodulation and transform the clinical landscape of neurodegenerative disease treatment.

Works Cited:

1. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017; 3(17013). doi:10.1038/nrdp.2017.13
2. Axelsen TM, Woldbye DPD. Gene therapy for Parkinson’s Disease, an update. J Parkinsons Dis. 2018;8(2):195-215. doi:10.3233/JPD-181331
3. Su D, Cui Y, He C, et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021. BMJ. 2025;388:e080952. doi:10.1136/bmj-2024-080952
4. Park J, Na YC, Lee J, et al. Role of P₂ × ₇ receptor during focused ultrasound induced blood brain barrier modulation. Sci Rep. 2025;15(1):965. doi:10.1038/s41598-024-83913-3
5. Mead BP, Kim N, Miller GW, et al. Novel focused ultrasound gene therapy approach noninvasively restores dopaminergic neuron function in a rat Parkinson’s disease model. Nano Lett. 2017;17(6):3533-3542. doi:10.1021/acs.nanolett.7b00616
6. Xhima K, Nabbouh F, Hynynen K, Aubert I, Tandon A. Noninvasive delivery of an   α-synuclein gene silencing vector with magnetic resonance-guided focused ultrasound. Mov Disord. 2018;33(10):1567-1579. doi:10.1002/mds.101
7. Yue P, Miao W, Gao L, Zhao X, Teng J. Ultrasound-triggered effects of the microbubbles coupled to GDNF plasmid-loaded PEGylated liposomes in a rat model of Parkinson’s disease.  Front Neurosci. 2018;12:222. doi:10.3389/fnins.2018.00222
8. Blesa J, Pineda-Pardo JA, Inoue KI, et al. BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging. Sci Adv. 2023;9(16):eadf4888. doi:10.1126/sciadv.adf4888