Blood-Brain Barrier Disruption using Focused Ultrasound in a Large Animal Model

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DESCRIPTION (Provided by Applicant): The blood-brain barrier (BBB) normally serves to protect the brain from agents that circulate in the blood. However, it also poses a major limitation to drug delivery and the large majority of drugs cannot be used in the central nervous system (CNS). Current methods to overcome the BBB are invasive, non-targeted, and/or require the development of new drug carriers. We have shown previously that short, low-intensity focused ultrasound bursts combined with a microbubble-based ultrasound contrast agent can result in targeted, temporary BBB disruption. Our prior studies in small animals have shown that this disruption can be achieved safely and that even large molecule agents can be delivered to the brain. This technique potentially could represent a fundamental change in the treatment of CNS disease, creating new opportunities for drug development and allowing new uses of currently available drug therapies. With this technology combined with medical imaging, one could develop truly image-guided drug delivery and achieve a drug concentration precisely tailored to an individual patient's CNS pathology. However, certain effects cannot be adequately measured in small animals with the technique. Reflection and standing wave effects and structures in the ultrasound beam path such as the ventricles and large blood vessels can potentially result in unwanted effects outside of the focal zone, and these risks cannot be evaluated in small animal models such as mice, rats, or rabbits. Before moving confidently to patient treatments with this technology, it is essential that its safety profile be established in an animal brain that can take these effects into account. Furthermore, it is possible that the ultrasound exposures can cause functional deficits, which also are difficult to establish in small animal models. Thus, the aim of this work is to perform a safety study of ultrasound-induced BBB disruption in a primate model. The BBB will be temporarily disrupted in rhesus macaques using a clinical MRI-guided focused ultrasound system, and we will evaluate the effects to the brain using MRI, histology, and functional tests. The purpose of this work will to be to perform a safety study in primates of a method that uses focused ultra- sound bursts and a microbubble agent to temporarily disrupt the blood-brain barrier at targeted locations. As the blood-brain barrier is currently a major limitation to the use of drugs for brain disorders, such a technique could have a major impact on healthcare. These experiments are needed to address potential safety issues with the technique that cannot be determined from small animal models.