Page 22 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

Table 7. Drug delivery with MB‑assisted US for clinical studies in Parkinson’s disease
References Drug, Dye, Patients US devices/ Targeted area MBs Therapy duration
Particle parameters
Gasca-Salas Gadolinium 5 patients ExAblate Neuro Right Luminity 2 sonications separated by
®
®
et al., 2021 117 MRgFUS system parieto-occipito- MBs (4 µL/kg) 2 – 3 weeks
temporal cortex
Pineda-Pardo Gadolinium 7 patients ExAblate Neuro Posterior putamen Luminity 2 sonications separated by
®
®
et al., 2022 118 MRgFUS system MBs (4 µL/kg) 2 – 4 weeks
®
®
Huang et al., Glucocerebrosidase 4 patients with ExAblate Neuro Putamen Definity MBs 1 sonication every
2022 120 (GCase) GBA1 mutations MRgFUS system; (4 µL/kg/5 min) 2 weeks for a total of
10 ms pulses, DC 1%, 3 sonications
0.5 MPa, for 2 min
®
®
Meng et al., Glucocerebrosidase 4 patients with ExAblate Neuro Putamen Definity MBs 1 sonication every
2022 121 (GCase) GBA1 mutations MRgFUS system; (4 µL/kg/ 2 weeks for a total of
10 ms pulses, DC 1%, 5 min) 3 sonications
0.5 MPa, for 2 min
Gasca-Salas Gadolinium 3 patients ExAblate Neuro Substantia nigra and Luminity MBs 2 sonications separated by
®
®
et al., 2024 119 MRgFUS system putamen (2.5 mL/min) 2 – 3 weeks
Abbreviations: DC: Duty cycle; MB: Microbubble; MRgFUS: Magnetic resonance imaging-guided focused ultrasound; US: Ultrasound.
initial symptoms: (1) bulbar-onset ALS, characterized by The SOD1 G93A transgenic mouse model typically develops
dysarthria and dysphagia; (2) spinal-onset ALS, marked by severe motor impairments by approximately 120 days of
spasticity, muscle weakness, and progressive atrophy of the age and succumbs to the disease around 160 days. In this
133
limbs. About 90% of ALS cases are sporadic, while 10% are study, Shen et al. targeted the motor cortex of SOD1 G93A
familial, involving at least two affected family members. mice with a US sequence (1.1 MHz, 1 Hz PRF, 9.09 ms burst
Up to 50% of ALS patients experience cognitive and/or length, 0.52 MPa) for 60 s using a lab-made US device after
behavioral impairments, and 13% develop frontotemporal an i.v. injection of lab-made lipid-shelled MBs (0.2 µL/g).
lobar dementia. 123 The treatment involved four intermittent, non-overlapping
To date, more than 30 causal genes have been implicated FUS exposures, with a 15-min interval between each
in the disease. 124,125 The most frequently involved genes application. Edaravone was administered alternately
are C9ORF72, Superoxide dismutase 1 (SOD1), TARDBP through i.v. and intraperitoneal routes (15 mg/kg) every
(TDP-43), and FUS. A key neuropathological hallmark 2 days, starting when the mice were 13 weeks old, for a
of ALS is the accumulation and aggregation of TDP-43 duration of 6 weeks. The results demonstrated that the
in the cytoplasm of motor neurons, which is observed in MB-assisted US achieved a two-fold increase in edaravone
nearly all ALS patients. However, it remains unclear how concentration within the motor cortex compared to
pathogenic variants in different genes converge to result the control condition. This acoustically mediated drug
in the same TDP-43 aggregation. The pathophysiology delivery significantly improved neuromuscular function
126
of ALS involved multiple mechanisms, including and reduced muscle atrophy compared to ALS mice treated
neuroinflammation, glutamate-mediated excitotoxicity, with edaravone without US. Importantly no tissue damage
oxidative stress, mitochondrial dysfunction, and alterations was observed, underscoring the safety of this approach.
in mRNA metabolism and protein homeostasis. 126-128 These This proof-of-concept study highlights the potential of
processes represent critical targets for the development MB-assisted US for targeted drug delivery in the treatment
of therapeutic molecules aimed a mitigating the disease’s of ALS (Table 8). 132
progression. 129-131
7.3. Clinical phase
7.2. Pre-clinical phase At present, a single clinical trial is investigating the
Recently, Shen et al. explored the use of edaravone in the feasibility, reversibility, and safety of transient BBB opening
132
SOD1 G93A mouse model of ALS, leveraging the MB-assisted using transcranial MRgFUS in ALS patients. Abrahao
76
US for enhancing drug delivery. SOD1 is a key antioxidant et al. targeted the primary motor cortex, specifically
76
enzyme that protects cells from the deleterious effects the precentral gyrus, marking the first attempt to target
of superoxide radicals. Dysfunction or aggregation of subcortical white matter regions in humans. The study
SOD1 protein contributes to the pathogenesis of ALS. involved four right-handed participants (two women and

Volume 11 Issue 2 (2025) 16 doi: 10.36922/jctr.24.00061