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Principal Investigator: Aria Pearlman Morales
Organization: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
Fiscal Year: 2024
Award: $53,974
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <2-dimensional><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Anti-Rejection Therapy><Awareness><Binding><Biocompatible Materials><Biomaterials><Blood Vessels><Cancers><Cardiac Diseases><Cardiac Disorders><Cardiac Transplantation><Cause of Death><Cell Body><Cell Coat><Cell surface><Cells><Chimerism><Clinical><Clinical Medical Sciences><Clinical Medicine><Clinical Skills><Communicable Diseases><Communication><Development><Diabetes Mellitus><Docking><Donor person><Dose><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drug toxicity><Endocytosis><Endothelial Cells><Endothelium><Evaluation><Formulation><Geography><Glycocalyx><Goals><Grafting Procedure><Health><Heart Diseases><Heart Grafting><Heart Transplantation><Heterotopic Transplantation><Human><Hyperlipemia><Hyperlipidemia><Hypertension><Image><Immune><Immune Tolerance><Immunes><Immunologic Tolerance><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive Therapy><Immunosuppressive drug><Immunosuppressive treatment><Implant><Incidence><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Interdisciplinary Research><Interdisciplinary Study><Lentivirinae><Lentivirus><Leucine Zippers><Life><Living Donors><Location><Malignant Neoplasms><Malignant Tumor><Mentors><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Nucleic Acids><Organ><Organ Donor><Organ Transplantation><Organ Transplants><Organ Viability><Organ failure><Pathway interactions><Patients><Peptides><Perfusion><Physicians><Physiologic><Physiological><R-Series Research Projects><R01 Mechanism><R01 Program><Research><Research Grants><Research Project Grants><Research Projects><Risk Factors><Scientist><Stress><Surface><Survival Rate><System><Technology><Therapeutic><Therapeutic immunosuppression><Thick><Thickness><Time><Toxic effect><Toxicities><Training><Transfection><Transplant Recipients><Travel><Treg adoptive therapy><Treg therapy><Trust><Vascular Endothelium><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Wait Time><Work><adoptive therapy of regulatory T cells><artificial immunosuppression><biological material><cardiac graft><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><density><developmental><diabetes><ex vivo perfusion><experiment><experimental research><experimental study><experiments><heart disorder><heart transplant><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><imaging><immune suppression><immune suppressive activity><immune suppressive agent><immune suppressive function><immune suppressor><immune system tolerance><immune unresponsiveness><immunological paralysis><immunosuppression therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunosuppressive substance><immunosuppressor><implantation><in vivo><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><malignancy><model of animal><mouse model><multidisciplinary><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><novel><nucleic acid delivery><nucleic acid therapy><nucleic acid-based therapeutics><organ allograft><organ graft><organ transplant patient><organ transplant recipient><organ xenograft><particle><pathway><personalized drugs><precision drugs><pressure><prevent><preventing><programs><restraint><shear stress><short interfering RNA delivery><siRNA delivery><side effect><skills><small interfering RNA delivery><therapeutic nucleic acids><trafficking><transplant donor><transplant model><transplant patient><two-dimensional><uptake><vascular>