A Bio-orthogonal Targeting System for Precision Drug Delivery to Vascular Endothelium in Transplanted Organs

Boston University (Charles River Campus), Boston MA

Investigators

Abstract

Project Summary and Abstract. The viability of a transplanted organ and the patient’s health are inherently limited by the burdens of immunosuppressive therapy, which must be used for the duration of the patient’s life. Systemic administration of these immunosuppressive agents increases the incidence of infectious disease and malignancy, which are the leading causes of death in transplant patients. While new tolerance induction strategies are evolving, like Treg therapies and mixed chimerism, they are limited in their ability to only be used for living donor transplants and difficulties in ex vivo culture and expansion. However, developments in the field of ex vivo machine perfusion of transplanted organs now offer unique therapeutic opportunities to treat donor organs prior to their implantation into the recipient. My work focuses on creating a system that leverages advances in ex vivo perfusion to install a bio-orthogonal surface targeting moiety on an organ, which is introduced to the organ via ex vivo perfusion during its time in transport. I hypothesize that this targeting system will allow for the systemic dosing of lipid nanoparticles that bind only to vascular endothelium expressing the bio- orthogonal target within the organ, therefore allowing for localized immunosuppression and immune tolerance induction, while minimizing the highly undesirable and toxic side effects of immunosuppressive drugs. Aim 1 of this proposal demonstrates the targeted drug delivery to vascular endothelium via lipid nanoparticle binding to permanently expressed bio-orthogonal moiety in two dimensional endothelial culture. Aim 2 includes the optimization and demonstration of the LNP targeting system to effectively deliver therapeutic cargo under physiological sheer stress and flow conditions. This will be performed in ex vivo perfused human blood vessels. Aim 3 harnesses the ability of the system to be utilized in a relevant heterotopic murine heart transplantation model as a proof-of-concept to demonstrate the ability for the targeted particles to localized to a transplanted organ. This proposal builds around four key components of critical research and clinical skills to support my development into an independent physician scientist: (1) an interdisciplinary research project focusing on a novel nucleic acid delivery system for the selective delivery of therapeutics to a transplanted organ (2) multi- disciplinary mentoring from Drs. Grinstaff (biomaterials, nanoparticles, drug delivery) and Osho (clinical medicine, animal models, and ex vivo perfusion), (3) academic physician scientist training in research conduct and communication skills, (4) clinical awareness program, overseen by Dr. Osho a na�onally recognized leader in the field. (5) professional development to guide my training goals.