BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

血液脳関門開放術による遺伝子治療法の開発 --身体を傷つけない脳疾患の治療を目指して--. 京都大学プレスリリース. 2023-04-20.Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders

Bifurcation of ensemble oscillations and acoustic emissions from early stage cavitation clouds in focused ultrasound

The acoustic emissions from single cavitation clouds at an early stage of development in 0.521 MHz focused ultrasound of varying intensity, are detected and directly correlated to high-speed microscopic observations, recorded at 1 × 106 frames per second. At lower intensities, a stable regime of cloud response is identified whereby bubble-ensembles exhibit oscillations at half the driving frequency, which is also detected in the acoustic emission spectra. Higher intensities generate clouds that develop more rapidly, with increased nonlinearity evidenced by a bifurcation in the frequency of ensemble response, and in the acoustic emissions. A single bubble oscillation model is subject to equivalent ultrasound conditions and fitted to features in the hydrophone and high-speed spectral data, allowing an effective quiescent radius to be inferred for the clouds that evolve at each intensity. The approach indicates that the acoustic emissions originate from the ensemble dynamics and that the cloud acts as a single bubble of equivalent radius in terms of the scattered field. Jetting from component cavities on the periphery of clouds is regularly observed at higher intensities. The results may be of relevance for monitoring and controlling cavitation in therapeutic applications of focused ultrasound, where the phenomenon has the potential to mediate drug delivery from vasculature