Focused Ultrasound Mediated Gene Therapy Delivery for the Treatment of Parkinson’s Disease
Background: Parkinson’s disease (PD) is a common neurodegenerative disorder that afflicts approximately 1% of the population aged 60 or older.1 Patients diagnosed with PD often present with symptoms such as bradykinesia, resting tremor, and cogwheel rigidity, which typically persist and worsen over time. Levodopa combined with carbidopa is the typical PD therapy but only treats symptoms and can lead to drug resistance. Gene therapies are effective but only available via invasive stereotactic injection delivery, which can cause adverse effects.2
Objective: In this narrative review, we explored the mechanisms and efficacy by which focused ultrasound (FUS) application with concurrent microbubble administration can selectively open the blood-brain-barrier (BBB) for intravenously delivered gene therapies to reach clinically relevant doses in the central nervous system.
Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “focused ultrasound”, ” gene therapy”, and ” Parkinson’s Disease”.
Results: The studies reviewed here deliver either non-viral gene therapies, such as glial cell-derived neurotrophic factor (GDNF) or nuclear factor E2-related factor 2, (Nrf2, NFE2L2) or viral gene therapies, such as AAV.SIRT3-myc (adeno-associated virus expressing myc-tagged SIRT3). The 6-hydroxydopamine (6-OHDA)-induced rat model of PD was used in all these studies and is a commonly used animal model to study the pathophysiology and therapeutic strategies for PD.3 Delivery of GDNF with FUS to the striatum led to an 11-fold increase in ipsilateral striatal GDNF protein compared to 6-OHDA only control animals. In the treated group, this protein increase translated to improvements in locomotor function retained through the 12–week duration of the experiment.3 Additionally, the apomorphine-induced rotational behavior was significantly reduced after glial cell line-derived neurotrophic factor (GDNF) plasmid (PLs-GDNF-MBs) treatment as compared to the PLs-MBs group. PLs-GDNF-MBs significantly up-regulated the scores in suspension and climbing pole tests when compared to PLs-MBs group.4 Quantitative PCR and western blot analysis showed that Nrf2 gene transfection reduced reactive oxygen species levels locally, thereby protecting neurons within the targeted region. Tyrosine hydroxylase and dopamine transporter expressions were partially rescued by Nrf2 transfection.5 Finally, MRI-guided-FUS mediated BBB permeabilization can be used to deliver AAV2.SIRT3-myc in the striatum but not the substantia nigra ipsilateral to the sonication site. Qualitative studies using immunofluorescence showed elevated levels of SIRT3-myc in the striatum.6
Conclusions: In summary, FUS can be a noninvasive method to deliver therapeutic genes to treat PD as it overcomes the limitations of invasive surgeries needed for traditional gene therapy methods. Studies have shown that this approach can improve motor symptoms and protect dopaminergic neurons in animal models. Further testing and optimization are needed to translate FUS into a clinically applicable, minimally invasive treatment option for PD and other neurological disorders.7
- Day, J. O. & Mullin, S. The Genetics of Parkinson’s Disease and Implications for Clinical Practice. Genes 12, (2021).
- Reich, S. G. & Savitt, J. M. Parkinson’s Disease. Med. Clin. North Am. 103, 337–350 (2019).
- Mead, B. P. et al. Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson’s Disease Model. Nano Lett. 17, 3533–3542 (2017).
- 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. 12, 222 (2018).
- Long, L. et al. Treatment of Parkinson’s disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles. Biochem. Biophys. Res. Commun. 482, 75–80 (2017).
- Trinh, D. et al. Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3. Drug Deliv. 29, 1176–1183 (2022).
- Meng, Y. et al. Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance-Guided Focused Ultrasound in Parkinson’s Disease: A Phase I Study. Mov. Disord. 37, 2134–2139 (2022).