Page 23 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

two men, with a median age of 61 years), assigned to either prevalence is 5 – 10/100,000 in North America and Europe,
the arm (n = 2) or leg (n = 2) target groups based on which with a higher rate observed in Western Europe. The
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limb exhibited greater weakness on the left side. On the day disease typically begins between the fourth to fifth decades
of the experiment, patients temporarily discontinued their of life and progressively worsens over 10 – 20 years,
usual ALS treatment (riluzole or edaravone) but resumed ultimately leading to death; however, it can also manifest
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them immediately after the procedure. Definity MBs before the age of 20. 136-138
(4 µL/kg) were administered intravenously, followed by HD is characterized by a combination of psychiatric,
exposure of the target region to US waves (center frequency: cognitive, and motor symptoms. Clinical signs include
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220 kHz) using the ExAblate Neuro 4000 system. An involuntary movement disorders (e.g., chorea and
acoustic power ramp test was conducted, followed by one dystonia) and voluntary movement impairments
to two 90-s sonication cycles to achieve BBB opening. (e.g., clumsiness, dysarthria, swallowing disorders,
During each cycle, the targeted brain tissue received a US falls, bradykinesia, rigidity). Cognitive impairments
sequence (center frequency of 220 kHz, pulse repetition often involve issues with memory, attention, judgment,
period of 300 ms, DC 0.88%) for each of the four spots reasoning, and comprehension, with dementia frequently
within the target region. Each cycle coincided with an i.v. developing over time. The hallmark symptom of HD is
injection of MBs. Abrahao et al., successfully demonstrated Huntington’s chorea, which involves involuntary jerking
the transient and safe acoustically mediated BBB opening and muscle twitching.
in ALS patients. Importantly, no serious adverse effects
(i.e., hemorrhage, edema, inflammation, or tissue damage) Neuropathological findings reveal significant
were observed 30- or 60-day post-treatment. neurodegeneration, with the selective loss of neurons in
the caudate and putamen of the basal ganglia. The disease
However, to date, no study has explored whether
combining the US with therapeutic molecules could is caused by an abnormal expansion of a CAG trinucleotide
repeat in the coding region of the HTT gene. This
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improve motor symptoms in ALS. Similarly, research mutation leads to an expanded polyglutamine stretch in the
on the therapeutic impact of US/therapeutic molecule N-terminal region of the Huntingtin protein, resulting in a
combinations in AD and PD has yet to address symptom toxic gain of function. 134,136 Despite the clear understanding
improvement comprehensively. This promising clinical of the genetic basis of HD, no curative treatment is currently
trial lays the foundation for further investigations into available. Existing therapeutic approaches focus primarily
MB-assisted US for therapeutic delivery in ALS treatment
(Table 9). 76 on managing chorea, but several novel treatments are
under active investigation. 103,139,140
8. Applications in Huntington’s disease (HD) 8.2. Pre-clinical phase

8.1. HD Despite the lack of a clinically approved treatment for HD,
HD, also known as Huntington’s chorea, is a progressive promising pharmacological approaches aimed at reducing
dominantly inherited neurodegenerative disorder. Its HTT protein levels have been explored to increase neuronal

Table 8. Drug delivery with MB‑assisted US for pre‑clinical studies in amyotrophic lateral sclerosis
References Drug, dye, Animal model US devices/parameters Targeted MBs Therapy duration
particle area
Shen et al., 2023 132 Edaravone SOD1 G93A mouse Lab-made US device; Motor cortex Lab-made 4 intermittent non-overlapping
1.1 MHz, 1 Hz PRF, lipid-shelled MBs sonication with a 15-min
9.09 ms burst length, (0.2 µL/g) interval between each other
0.52 MPa for 60 s
Abbreviations: DC: Duty cycle; MB: Microbubble; PRF: Pulse repetition frequency; US: Ultrasound.

Table 9. Drug delivery with MB‑assisted US for clinical studies in amyotrophic lateral sclerosis
References Drug, Dye, Patients US devices/parameters Targeted area MBs Therapy
Particle duration
Abrahao et al., Gadolinium 2 women and ExAblate Neuro 4000 system; center Primary motor Definity MBs 1 sonication
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2019 76 2 men frequency of 220 kHz, pulse repetition cortex (4 µL/kg)
period of 300 ms, DC of 0.88% for 90 s
Abbreviations: DC: Duty cycle; MB: Microbubble; US: Ultrasound.

Volume 11 Issue 2 (2025) 17 doi: 10.36922/jctr.24.00061