The objective of the proposed research is to develop a precision T-regulatory cell (Treg)-based treatment to prevent growth and rupture of abdominal aortic aneurysms (AAA), a leading cause of death in developed countries. AAA result from uncontrolled inflammation.Thus, modulation of aortic specific inflammation could lead to the development of medical treatment for AAA, thereby delaying or preventing the need for surgical intervention and ultimately removing the risk of aneurysm-related death. Tregs are vital in preventing autoimmune diseases and promoting resolution of immune response. Recently, Chimeric Antigen Receptors (CARs) have been used to generate precision therapy by directing T-cells to bind and activate at specific locations within the body. We therefore hypothesize that we can engineer a CAR to be expressed in Tregs that will direct them to bind to damaged aortic tissue and block the inflammatory process. Elastin Binding Protein (EBP) is an endogenous receptor that directs inflammatory cells to damaged aortic tissue in humans. Consequently, EBP is an ideal candidate to direct Tregs to damaged aortic tissue in AAA patients as a key component of a CAR. Our team has significant experience studying vascular inflammation, AAA, and Treg biology, and has successfully engineered CARs in the past. Based on our collective expertise we propose to investigate two Specific Aims to characterize the interaction of Tregs and damaged aortic tissue and generate an engineered Treg to be used to treat AAA:
Aim 1 : Genetically modify Tregs to express an EBP- CAR that targets damaged elastin in aortic tissue.
Aim 2 : Evaluate the binding capacity and activation of Tregs and genetically modified Tregs to aortic tissue from patients with aortic aneurysms. We believe these studies will allow us to gain a more in-depth understanding of the interaction between Tregs and damaged aortic tissue, while developing an innovative strategy to oppose vascular inflammation. If successful, this work will allow us to generate a CAR-Treg that can be tested for efficacy in animal models of AAA and potentially be translated into a novel therapeutic tool for the treatment of AAA, a disease that currently lacks effective medical treatment options. ! !
Abdominal Aortic Aneurysms (AAA) are a leading cause of the death worldwide for which surgery is the only treatment and many patients are not candidates. The proposed project aims to generate a chimeric antigen receptor to direct T-regulatory cells to injured aortic tissue and reduce the vascular inflammation that results in AAA growth and rupture. This novel approach will have the potential to develop a medical therapy to prevent aneurysm-related morbidity and mortality.