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Journal of Clinical and
Translational Research US-mediated drug delivery

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The NaviFUS system also integrates a real-time PCD brain metastases ) and neurodegenerative diseases (e.g.,
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device to manage the acoustic energy in real-time during ALS, AD, and PD 74,76 ).
the procedure. Pre-clinical studies have demonstrated the After reviewing the state-of-the-art of acoustically
safety and efficacy of BBB disruption using NaviFUS mediated therapeutic delivery using MBs or NDs – including
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in both small and large animal models. 70,71 Notably, the the biophysical mechanisms, sonoresponsive agents, and
BBB disruption is reversible within 24 h. At present, the US devices – we will now turn our focus to the application
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NaviFUS system is under clinical investigation specifically of this US modality for the treatment of neurodegenerative
for the treatment of recurrent glioblastoma. 57,71,72 diseases. First, we will provide the definition of these
4.2.3. ExAblate Neuro ® diseases, followed by a detailed discussion of pre-clinical
and clinical investigations of these diseases using this
InSightec Ltd. (Israel) has developed an MRI-guided FUS US-based approach.
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(MRgFUS) system known as ExAblate Neuro . Similar
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to the NavisFUS system, this extracorporeal MRgFUS 5. Applications in AD
device delivers noninvasive acoustic energy into targeted
brain tissues through the intact skull. The ExAblate 5.1. AD
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Neuro Type 1.0 system was originally designed to treat AD is the most common neurodegenerative disorder,
essential tremor and PD by partially ablating the thalamus characterized by its progressive and fatal nature. In 2000,
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through acoustically mediated thermal ablation at a center AD affected 15.3 million people worldwide, a number
frequency of 0.65 MHz. Later, this system was adapted projected to rise to 63 million by 2030. It represents a
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to enhance the native BBB permeability for therapeutic growing global health challenge, with an annual incidence
delivery to targeted brain tissues at a center frequency of of 1.8 million cases in the USA and Europe. AD progresses
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0.220 MHz, now referred to as ExAblate Neuro Model as a continuum, with stages that vary in duration for each
4000 Type 2.0. patient: (1) The pre-clinical or prodromal stage, where no
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The ExAblate Neuro system consists of a high-field 3T clinical symptoms are apparent, but biomarkers such as
MRI scanner and a hemispherical 1,024-element phased amyloid-tau-neurodegeneration can be detected; (2) The
array US transducer, which is integrated with computer mild cognitive impairment stage, during which symptoms,
systems. These systems utilize computed tomography such as memory, language, and thinking difficulties emerge
(CT) scan data to align, steer, and control the transducer but do not significantly interfere with daily life; and (3) The
array (Figure 9). Before FUS exposure, the treatment dementia stage, marked by a loss of autonomy, further
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parameters are precisely planned for each patient based categorized into mild, moderate, and severe levels.
on anatomical and functional data of cranial bone and The progression from the pre-clinical stage to the onset
target brain tissues provided by MRI and CT scans. of dementia can span 15 – 25 years. AD is characterized
During the intervention, the awake patient lies on an MRI- by the extracellular accumulation of beta-amyloid protein
compatible robotic positioning table, with the patient’s fragments, forming clumps known as beta-amyloid
head is immobilized in a stereotactic frame to prevent plaques, and the intracellular accumulation of an abnormal
any movement during the procedure, which lasts between form of the tau protein known as tau tangles. Amyloid-β
2 and 4 h. The stereotactic frame enables precise target (Aβ) is believed to play roles in synaptic homeostasis,
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selection and intraoperative MRI confirmation, ensuring immunity, and lipid processing. However, abnormal
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electronic steering of the FUS beam with submillimeter cleavage of the amyloid pre-cursor protein by β- and
accuracy (<1 mm) to one or multiple brain targets, as γ-secretases results in the production of Aβ peptides,
defined by the planned volume geometry. US sequences which form the core of plaques. Tau protein is crucial for
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are initiated immediately after the i.v. injection of MBs. The microtubule stabilization, axonal transport, and signaling
MRI scanner precisely guides the US beam to the targeted pathway modulation. Abnormal phosphorylation of tau
brain regions during the procedure, and the BBB opening leads to its aggregation, disrupting pre-synaptic and post-
is monitored using DCE-MRI after the i.v. administration synaptic compartments by altering signaling cascades,
of gadolinium-based contrast agents. Notably, the BBB mitochondrial function, and axonal transport, ultimately
disruption is reversible within 20 h. causing neurotoxicity. The presence of Aβ plaques and
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Clinical investigations have demonstrated the safety and tau tangles is linked to chronic neuroinflammation and
efficacy of BBB disruption using the ExAblate Neuro system. progressive synaptic and neuronal loss.
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At present, this system is undergoing clinical trials for the These aggregates remain the main targets for the
treatment of brain tumors (e.g., recurrent glioblastoma and development of imaging tracers and therapeutic molecules.

Volume 11 Issue 2 (2025) 10 doi: 10.36922/jctr.24.00061