PROJECT SUMMARY/ABSTRACT Inherited Retinal Diseases (IRDs) are estimated to affect 1:2000 people, costing $13 billion to $32 billion in the United States alone. Much of this loss is in the form of lost wellbeing and patient experience, necessitating treatment methods. Recent scientific advances have produced gene therapies to treat IRDs, but these treatments require highly trained surgeons to administer, and can cause damage to the retinal tissue. If these therapies could be delivered noninvasively, it would substantially reduce the risk profile and change the paradigm of drug delivery to the eye. Delivering therapeutics to the retina is difficult because the blood-retina barrier (BRB) prevents most macromolecules from exiting circulation. Recent work has displayed to ability of focused ultrasound (FUS) to open the BRB. Having preliminarily replicated these results through my own work, I am proposing using eternal markers of the eye to apply FUS to the entire retina at lower pressures and a higher ultrasound frequency to allow for safe BRB opening (FUS-BRBO) for viral delivery. One potential concern with gene therapies is off-target exposure, so the Szablowski lab has pioneered a new vector, called “AAV.FUS”, which has shown 10-15 fold improvement in brain specificity when used with focused ultrasound blood-brain barrier opening. We hypothesize that we will be able to optimize the parameters for FUS to allow BRBO without tissue damage and gene delivery across the layers of retina, with improved transduction efficiency of AAV.FUS and virally mediated cell type specificity. This project is separated into two aims: 1) Demonstrate safe and effective FUS-BRBO with enhanced precision across large regions of the retina, and 2) Evaluate AAV.FUS as a viral vector for treating retinal disease. Through our efforts, I will validate a novel drug delivery method for retinal diseases which I am calling Enhanced Transretinal Ultrasound Delivery (ETUDe). Use of ETUDe will simplify the process of treating retinal diseases though intravenous application of the drug, rather than the complex surgical procedure of subretinal or intravitreous injections. This development will be possible through a collaboration between the labs of Jerzy Szablowski and Benjamin Frankfort, which will leverage expertise in ophthalmology, non-invasive neuroscience, and genetic engineering. Together, these labs form an environment that is ideally-suited for this project, and has all the necessary equipment, skills, and expertise necessary for success.

PROJECT NARRATIVE Recent medical advances have developed a number of treatments for ocular disease from gene therapies to biologics; both of these have to be administered through direct injection into the subretinal or intravitreal space. Other research has investigated the use of focused ultrasound to disrupt the blood-brain barrier, so that therapeutics can be noninvasively delivered to the brain. We propose the use of this focused ultrasound to the eye so that drugs can move from systemic circulation into the eye in a technique we are calling Enhanced Transretinal Ultrasound Delivery (ETUDe).