Dose Response/Dynamics Ultrasound Mediated BBB Opening

DESCRIPTION (provided by applicant): A wide range of brain disorders are inaccessible to therapeutic agents because of the blood-brain barrier (BBB). The BBB prevents most large molecule drugs and gene preparations from entering into brain tissue. A method to safely and reversibly change the permeability of the BBB is therefore needed. Preliminary data show that ultrasound can be used to reversibly increase the permeability of the BBB for large molecules. The proposed research is a step towards developing a device that can deliver therapeutic agents to the brain in a clinical setting. We will use long exposures to low-intensity ultrasound to change the permeability of the blood-brain barrier in a rat model. The first aim of this research is to identify how adjusting the pulse duration of an ultrasound signal can improve delivery of a therapeutic agent across the blood-brain barrier. Passage of an adenoviral vector carrying a reporter gene for lacZ into brain tissue is measured by enzyme histochemistry, PCR, bioluminescence and quantitative RT-PCR. Localization of virus penetration is determined by immunohistochemistry and fluorescence microscopy. The second aim is to identify the time course of the BBB opening. An understanding of when BBB opening occurs during ultrasound application is needed to minimize ultrasound exposure and optimize drug delivery. Application of the virus at different time intervals after initiation of ultrasound exposure and measuring resulting vector concentration allows us to identify the dynamics of the BBB opening process. Public Health Relevance: Many brain diseases are difficult to treat because a barrier around the brain's blood vessels prevents most drugs from entering the brain. We aim to develop a device that will safely and reversibly open this barrier, allowing drugs to enter the brain and thereby creating an opportunity to treat diseases like brain cancer, Alzheimer's, Parkinson's, and others.