Site-Specific Brain Therapeutics

​Identifying the correct brain site for invasive brain therapy is a major challenge. How can we be sure that the brain region targeted for surgery will benefit the patient? Could we noninvasively test that site by modulating its activity for a few days, for example, to show improvement in epilepsy without side effects?

    To achieve this, we developed a new technology called Regionally-Activated Interstitial Drugs (RAID) for noninvasive, non-genetic, site- and molecularly-specific neuromodulation in the intact brain. This innovative approach aims to enable precise testing. RAID utilizes focused ultrasound to induce localized blood-brain barrier opening (FUS-BBBO), facilitating the site-specific delivery of a protein enzyme into targeted brain regions. We engineer this enzyme to bind to the brain interstitium, allowing it to remain within the brain for several days. This enzyme can locally convert an inert BBB-permeable prodrug into a neuroactive drug, modulating neuronal activity for days after a single BBB opening procedure. The RAID paradigm is versatile and can be applied to any enzyme and prodrug pair to control various aspects of central nervous system physiology.

    In this highly translational project, we will further develop RAID as a noninvasive, safe procedure to study neural circuitry and ‘test-drive’ brain therapies. This includes extending the retention of delivered enzymes in the brain interstitium, enhancing enzyme catalytic efficiency and tissue specificity, and evaluating efficacy and safety in animal disease models.