Kwon, N. | Search bioRxiv

bioRxiv2024

Focused ultrasound enhanced antibody delivery for the treatment of Parkinson's Disease

Treatment of neurological disorders is partly impeded by the size of large pharmacological agents which are thereby unable to bypass the blood-brain barrier (BBB). Focused ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to safely, non-invasively and transiently open the BBB, allowing the passage of large biomolecules to the brain parenchyma through the otherwise impermeable barrier. This pilot study assessed the feasibility of FUS-mediated delivery of an anti-alpha-synuclein (-syn) monoclonal antibody (mAb) in Parkinsons disease (PD) mouse models that exhibit -syn aggregates. Mice (n=21) underwent FUS on a weekly basis over the course of 2-3 weeks, followed by a one-month survival period. MRI and microscopy were performed to confirm BBB opening with FUS and visualize antibody delivery. Safety was assessed in vivo using passive cavitation detection and immunohistochemistry to evaluate microglial and astrocyte activity ex vivo. It was found that treatment sessions for multiple FUS sessions of targeted antibody delivery was feasible in alpha-synuclein models facilitating immunotherapeutics for PD.

neuroscience↗

bioRxiv2024

Functional ultrasound (fUS) imaging of displacement-guided focused ultrasound (FUS) neuromodulation in mice

Focused ultrasound (FUS) stimulation is a promising neuromodulation technique with the merits of non-invasiveness, high spatial resolution, and deep penetration depth. However, simultaneous imaging of FUS-induced brain tissue displacement and the subsequent effect of FUS stimulation on brain hemodynamics has proven challenging thus far. In addition, earlier studies lack in situ confirmation of targeting except for the magnetic resonance imaging-guided FUS system-based studies. The purpose of this study is 1) to introduce a fully ultrasonic approach to in situ target, modulate neuronal activity, and monitor the resultant neuromodulation effect by respectively leveraging displacement imaging, FUS, and functional ultrasound (fUS) imaging, and 2) to investigate FUS-evoked cerebral blood volume (CBV) response and the relationship between CBV and displacement. We performed displacement imaging on craniotomized mice to confirm the in targeting for neuromodulation site. We recorded hemodynamic responses evoked by FUS and fUS revealed an ipsilateral CBV increase that peaks at 4 s post-FUS. We saw a stronger hemodynamic activation in the subcortical region than cortical, showing good agreement with the brain elasticity map that can also be obtained using a similar methodology. We observed dose-dependent CBV response with peak CBV, activated area, and correlation coefficient increasing with ultrasonic dose. Furthermore, by mapping displacement and hemodynamic activation, we found that displacement colocalizes and linearly correlates with CBV increase. The findings presented herein demonstrated that FUS evokes ipsilateral hemodynamic activation in cortical and subcortical depths and the evoked hemodynamic responses colocalized and correlate with FUS-induced displacement. We anticipate that our findings will help consolidate accurate targeting as well as an understanding of how FUS displaces brain tissue and affects cerebral hemodynamics.

bioengineering↗

bioRxiv2022

Focused ultrasound-mediated brain genome editing

Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

bioengineering↗