Page 24 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

survival and improve motor functions. To date, there are for the delivery of an AAV9 viral vector encoding the
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three pre-clinical studies and no clinical trials investigating miR10150, a microRNA targeting HTT transcripts for
i.c. drug delivery using MB-assisted US for HD. Burgess degradation, along with green fluorescent protein (GFP)
et al. examined the therapeutic potential of delivering as a reporter gene. Following the i.v. injection of Optison
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cholesterol-conjugated anti-Htt siRNA (cc-siRNA- MBs (100 µL/kg), US waves (1 Hz, 10 ms, 0.34 MPa) were
Htt) into the striatum of an HD mouse model through applied to the striatum (right caudate putamen) of zQ175
MB-assisted US (lab-made MRgFUS device; center mice for 120 s using a lab-made US device. The AAV9 viral
frequency of 558 kHz, burst length of 10 ms, PRF of 1 Hz, vectors were administered intravenously immediately after
0.3 MPa). Definity MBs (0.02 mL/kg) were administered US exposure. Analysis of GFP expression in brain tissue
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intravenously, followed by immediate US exposure to confirmed the feasibility and efficiency of MB-assisted US
the striatum for 120 s. Then, cc-siRNA-Htt was injected for delivering AAV9 viral vector in both HD and wild-type
through either a tail vein catheter or an intra-carotid mice at ages 2, 6, and 12 months. However, Owusu-Yaw
catheter. BBB opening was monitored using DCE-MRI. et al. did not evaluate the i.c. production of miR10150 or
This protocol involved two US exposures separated by a its therapeutic benefit (Table 10).
1-h interval, and the mice were sacrificed 48 h later. The
results demonstrated that MRgFUS successfully delivered Altogether, these findings demonstrate that MB-assisted
the cc-siRNA-Htt to the striatum, resulting in a significant US is a promising modality for the delivery of therapeutics
32% reduction in Htt gene expression, regardless of the in the treatment of HD.
route of administration. However, this pre-clinical
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study did not assess whether the enhanced bioavailability 9. Discussion
of cc-siRNA-Htt led to increased neuronal survival or Accessing the brain for drug delivery remains a significant
improved motor functions in HD mice. challenge in the treatment of neurodegenerative diseases.
In another study, Lin et al. utilized the MB-assisted BBB opening is a rapidly expanding field, as evidenced
115
US to boost i.c. production of GDNF in the R6/2 mouse by the growing number of publications on this topic. This
model of HD. A liposomal formulation of GDNF- method first emerged in the early 2000s with Hynynen’s
26
encoding pDNA was administered intravenously, followed publications on BBB disruption in a rabbit model, and a
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by the injection of SonoVue MBs (0.1 mg/kg). The new momentum has been achieved thanks to advances in
striatum was then exposed to a US sequence (lab-made US the understanding of the mechanisms and composition of
device; 1Hz PRF, 10 ms burst length, DC 1%, 0.33 MPa) MB/ND, the development of new transducer models, and
for 30 s in the contralateral hemisphere and for 60 s in the emergence of clinically approved devices in the 2010s.
the ipsilateral hemisphere. This approach significantly Many pre-clinical studies have demonstrated the safety,
increased i.c. GDNF protein levels, enhancing neuronal feasibility, and reversibility of opening the BBB. Among
plasticity and cell numbers. It also delayed symptom these, two studies have focused on the delivery of gadolinium
onset and improved motor impairments in the treated in animal models of neurodegenerative diseases, 63,87
group compared to the control group. Similarly, Owusu- while others have investigated the delivery of therapeutic
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Yaw et al. investigated the efficacy of MB-assisted US molecules to assess their effects on behavior. 112,115,132 A few
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Table 10. Drug delivery with MB‑assisted US for pre‑clinical studies in Huntington’s disease
References Drug, dye, particle Animal US devices/parameters Targeted MBs Therapy duration
model area
Burgess et al., cc-siRNA-Htt Rat Lab-made MRgFUS device; center Striatum Definity MBs 2 sonications at 1-h
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2012 134 frequency of 558 kHz, burst length (0.02 mL/kg) interval
of 10 ms, 1 Hz PRF, 0.3 MPa
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Lin et al., 2019 115 GDNF R6/2 mouse Lab-made US device; 1Hz PRF, Striatum SonoVue MBs 1 sonication
10 ms burst length, DC 1%, (0.1 mg/kg)
0.33 MPa for 30s at the contralateral
hemisphere and for 60s
Owusu-Yaw et al., AAV9 viral zQ175 mouse Lab-made US device; 1 Hz, 10 ms, Striatum Optison MBs 1 sonication,
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2024 135 vector encoding 0.34 MPa for 120 s (100 µL/kg) sacrifice 3 weeks
the microRNA, later
miR10150
Abbreviations: DC: Duty cycle; MB: Microbubble; MRgFUS: Magnetic resonance imaging-guided focused ultrasound; PRF: Pulse repetition frequency;
US: Ultrasound.

Volume 11 Issue 2 (2025) 18 doi: 10.36922/jctr.24.00061