Transplantation is a highly successful therapy for end-stage renal disease but there is a significant shortage of available donor organs that has forced utilization of low-quality kidneys to save patients lives. Extending the donor criteria has coincided with a growing appreciate that factors associated with organ donation, procurement and storage greatly affect post-transplantation outcomes. Unlike heart transplantation, kidney donors can be derived from a variety of sources that include living donors, donation after brain death, and donation after cardiac death. However, the vast majority of kidneys are donated from deceased donors and donation after brain death or after cardiac death predispose poorer post-transplantation outcomes. Problems inherent to organ transplantation, such as ischemia and extended cold storage, also negatively affect and cause irreparable damage to the donor kidney. These injurious events are known to elicit endothelial cell (EC) dysfunction, inflammation, and organ injury that are further exacerbated upon implantation by ischemia reperfusion injury (IRI) while also priming the donor organ for alloimmune recognition. While cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation by slowing metabolism to prevent cell death, current formulations do not minimize organ injury associated with cold storage or ischemia reperfusion injury. Vascular endothelum, which serves as a dynamic interface between the allograft and the recipient, is the initial target of the deleterious events that adversely affect graft health and function. Since gap and tight junctions regulate EC functionality, therapeutic strategies that promote the molecular and cellular integrity of endothelium of donor kidneys could preclude the mechanisms responsible for allograft damage and failure. FirstString Research Inc. has identified, characterized, and clinically-evaluated a novel peptide mimetic of connexin43, alpha-Connexin Carboxy-Terminal (aCT1), that stabilizes the gap and tight junctions of ECs during wound healing processes, leading to coordination of cellular communication, dampened inflammatory responses, reduced immune cell infiltrate, and enhanced regenerative properties. aCT1s small, stable, soluble design facilitates direct translocation into cells for intracellular drug delivery. Preliminary studies in clinically relevant models of kidney, heart, and lung transplantation reveal that aCT1 supplementation to standard-of-care organ preservation solutions stabilizes cellular junctions to protect EC from injurious effects of IRI and extending cold storage time. We hypothesize that cold preservation induces cell junction damage, which leads to EC dysfunction, inflammation, and renal damage upon reperfusion, and that supplementation of the therapeutic aCT1 peptide to standard of care preservation solution will preserve cell junctions, thereby improving renal health and function leading to superior post-transplantation outcomes. Here we propose to investigate the effect of ex vivo aCT1 pretreatment on donor kidney function, inflammatory state, and tissue injury using clinically relevant pig kidney transplantation models and low-quality human kidneys.
Public Health Relevance Statement: Project Narrative Transplantation is the most successful treatment for end-stage renal disease but there is a significant shortage in available donor kidneys requiring the utilization of low-quality organs to save the lives of patients. The mode of donor death, length of organ storage time, and surgical implantation all adversely affect survival post- transplantation. Here we propose to supplement standard of care preservation solution of donor kidneys with a novel therapeutic, aCT1, to prevent organ injury while promoting function, thereby optimizing the quality of the donor organ for transplantation leading to superior post-transplant outcomes.
Project Terms: Adverse event; Affect; Age; Allografting; Animal Model; Antibodies; Aorta; Bilateral; Biological; Biopsy; Blood Vessels; Brain; Brain Death; Cadaver; Cardiac Death; Cardiovascular system; Cell Death; cell injury; Cell physiology; cell type; Cells; Cessation of life; Clinical; Clinical Research; clinical translation; clinically relevant; Communication; Connexin 43; Connexins; Cryopreservation; Data; delayed graft function; design; Drug Delivery Systems; End stage renal failure; Endothelial Cells; Endothelium; Event; Failure; Family suidae; Formulation; Functional disorder; functional restoration; Gap Junctions; Gene Expression; Gold; graft failure; Health; Heart Transplantation; Heart-Lung Transplantation; Hour; Human; implantation; improved; Incidence; indexing; Inflammation; Inflammatory; Inflammatory Response; Infusion Pumps; Injury; Injury to Kidney; Intercellular Junctions; Ischemia; Kidney; kidney cell; Kidney Transplantation; Length; Living Donors; Measures; Metabolism; Modeling; Molecular; negative affect; Nephrectomy; novel; novel therapeutics; Operative Surgical Procedures; Organ; Organ Culture Techniques; Organ Donations; Organ Donor; organ injury; Organ Preservation Solutions; Organ Transplantation; Outcome; Patients; Peptides; peptidomimetics; Phase; post-transplant; pre-clinical; preservation; prevent; Price; Process; programs; Property; Pulsatile Flow; regenerative; renal damage; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; research clinical testing; Resistance; Risk; Rodent Model; Small Business Innovation Research Grant; Source; standard of care; Supplementation; System; Therapeutic; Tight Junctions; Time; tissue injury; transplant model; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Vascular Permeabilities; wound healing
