Gabriella Kabboul
BME PhD Proposal Presentation
Date: 2024-08-12
Time: 11:00 AM-1:00 PM
Location / Meeting Link: HSRB II N100 / https://emory.zoom.us/j/96428819798
Committee Members:
Rebecca D. Levit, MD (Advisor); Andrés J. García, PhD; Christopher B. Doering, PhD; Roger J. Hajjar, MD; Vahid Serpooshan, PhD.
Title: Epicardial Hydrogel Delivery for Cardiac Gene Therapy
Abstract:
Heart disease is the leading cause of death in the United States. Despite progress in cardiac gene therapies, the use of adeno-associated virus (AAV) to deliver genes to the heart has been largely unsuccessful due to poor transduction of cardiomyocytes and pre-existing anti-AAV immunity. Further complicating clinical translation, standard delivery techniques result in poor on-target gene transfer and vector leakage into systemic circulation resulting in off-target distribution and immune-mediated anti-vector responses. Many efforts to overcome these hurdles have resorted to utilizing large vector dosages which are highly toxic and have resulted in patient mortality. Local delivery to constrained sites with anatomic barriers to circulation and some immune cells have been successful, but such strategies have not been deeply explored for cardiac applications. Thus, a localized efficient delivery method to the heart may improve cardiac gene therapy outcomes. The pericardial space may be an attractive location for gene delivery given its lack of vascular access and minimal immune cell presence. We have previously engineered poly(ethylene glycol) (PEG) based hydrogels encapsulating non-viral cargo and shown the delivery to the epicardium through the pericardial space effectively target the heart with minimal off-target expression. This technique may successfully be applied for AAV-based therapies. PEG hydrogels are synthetic biomaterials that may be tuned for customizable release profiles. Epicardial hydrogel vector delivery may result in longer cardiac tissue residence time and minimal off-target effects which will reduce immunological responses to AAV. Follistatin-like 1 (FSTL1) is a validated epicardial gene target that augments cardiac regeneration after injury. The objective of this proposal is to engineer an epicardial hydrogel for optimal cardiac gene targeting and to evaluate our novel gene administration route using a promising gene candidate in a myocardial infarction (MI) model. We hypothesize that epicardial hydrogel delivery of AAV encoding FSTL1 will localize transgene expression to the epicardium, escape AAV immune responses, and induce cardiomyocyte proliferation, thereby rescuing cardiac function after MI. We will test our hypothesis in three aims. In aim 1, we will engineer AAV-containing gels with different release kinetics for enhanced cardiac gene delivery. In aim 2, we will evaluate the immunological responses to epicardial hydrogel delivery. In aim 3, we will test the therapeutic efficacy of epicardial gels for cardiac gene therapy. These results will establish an optimized epicardial AAV hydrogel delivery conquering physiological and immunological barriers in cardiac gene therapy.