Page 25 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

studies achieved both objectives, with most demonstrating neurodegenerative diseases and has only been used for
enhanced i.c. delivery of therapeutics and improvements in brain tumors, such as glioblastoma. 72,142 Similarly, the
cognitive functions. There is a notable preference for using SonoCloud system has only been tested in one clinical
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MRgFUS in pre-clinical studies; however, the majority has trial for AD as of 2022. ExAblate Neuro remains the
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been conducted on small animals, primarily rodents such most widely used system, including in a pre-clinical trial
as mice and rats. Only one study to date has utilized a large involving a non-human primate. The non-invasive
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animal model, specifically a non-human primate, within nature of MRgFUS and its relatively short intervention
the context of PD. Expanding pre-clinical research to times (2 – 4 h) make it an attractive option for research.
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include large animals could significantly enhance the However, its use entails significant logistical challenges,
understanding of BBB opening and lend greater weight to particularly due to the reliance on MRI. An MRI system
the results. In addition, rodent models, whether transgenic must be on-site, available for the procedure, and operated
or induced through neurotoxic lesions such as MPTP or by experienced personnel, all of which contribute to the
6-OHDA, have inherent limitations, posing challenges in high costs associated with this approach.
interpreting results and extrapolating findings to humans.
A major limitation across these studies is the variation
Compared to pre-clinical trials, most clinical studies in protocols. Both in the pre-clinical and clinical phases,
involving BBB disruption do not focus on drug delivery. the use of MBs/NDs, US devices, and parameters lack
Instead, they primarily assess the feasibility, safety, consistency, resulting in limited reproducibility between
and reproducibility of BBB opening in patients with studies. Differences are evident in the type of MBs used
neurodegenerative disease. 74,76,119 Notably, one study in (i.e., lab-made, SonoVue , Definity , Optison , and
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PD investigated glucocerebrosidase (GCase), 120,121 while Sonazoid ) as well as in their method of administration.
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another in AD evaluated the delivery of aducanumab. MBs are sometimes injected as a bolus and at other times as
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These recent studies are promising for the advancement an infusion. O’Reilly et al. compared BBB disruption in
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of BBB opening techniques in neurodegenerative diseases. vivo using a long infusion (2 min) versus a bolus injection
However, all clinical trials conducted thus far have involved (15 s) of Definity MBs at the same dose. Their findings
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a very small number of participants, typically ranging from revealed better BBB disruption with bolus injection,
3 to 9, which is surprising given the high prevalence of these attributed to the higher peak concentration of MBs in
conditions. To reliably evaluate the efficacy of therapeutics the circulation during bolus administration. The method
in humans, future studies need to include larger patient of administering therapeutics alongside MBs also varies.
cohorts to determine whether BBB opening significantly In clinical practice, sequential administration – infusion
enhances therapeutic effects compared to treatment alone. of the therapeutic treatment followed by bolus injection
It is worth noting that no standardized treatment exists for and sonication – is often preferred for the convenience
neurodegenerative diseases, and therapeutic responses vary of both healthcare staff and patients. 96,121 This method is
widely among patients. If a significant effect is not observed similarly adopted in pre-clinic phases, with MBs typically
with BBB opening, it may not necessarily reflect a limitation administered as a bolus rather than an infusion. Additional
of the technique but rather resistance to the treatment protocol variations include the use of loaded or unloaded
itself. Future studies should therefore not only focus on MBs, as well as targeted versus non-targeted MBs. At present,
the feasibility of the technology but also prioritize clinical there is insufficient data to compare the therapeutic efficacy
outcomes such as preserving memory, cognition, or motor of drug-loaded versus unloaded MBs in neurodegenerative
functions in patients with neurodegenerative diseases. diseases. Few pre-clinical studies explore this comparison,
One of the key challenges in slowing the progression of and no drug-loaded MBs have been clinically approved,
these diseases lies in their neurobiological characteristics. making such comparisons impossible in clinical trials.
Diseases such as PD and ALS are more localized, whereas Another challenge is the small sample size in clinical
conditions, such as AD are diffusive. Targeted diseases are trials, which limits the ability to draw rigorous or
seemingly easier to treat, as neurodegeneration is confined generalized conclusions about the therapeutic efficacy of
to a specific or limited region in the brain, allowing the US molecules delivered through sonoporation. In pre-clinical
to be focused on these areas. In contrast, treating diffuse studies, researchers often use ab-made MBs, allowing
diseases is more complex, as all affected regions would greater flexibility in loading or tagging MBs. In contrast,
require treatment with FUS. clinical trials must use clinically approved MBs, which
There is also a noticeable preference for clinically restricts this flexibility. Beyond MB characteristics, US
approved devices in this field. For instance, the parameters also vary widely between studies. Sonication
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NaviFUS system has not been used in clinical trials for duration may range from 30 s to 2 min, with acoustic

Volume 11 Issue 2 (2025) 19 doi: 10.36922/jctr.24.00061