A Hydrogen Sulfide Delivery Technology for Organ Preservation Therapy

Project Summary/Abstract Nearly 1 in 3 people with diabetes and 1 in 5 people with high blood pressure suffer from chronic kidney disease (CKD), while approximately 2 in 1,000 Americans are living with end-stage kidney disease (ESKD)—kidney failure that is treated with a kidney transplant or dialysis. Despite the high cost of transplantation, there are nearly 100,000 patients waiting for transplantable kidneys each year in the US and only 1:6 patients receive a transplant. The shortage in viable donor kidneys results in significant mortality in the ESKD patient population. Ischemia-reperfusion injury (IRI) is a barrier to successful transplant surgery and an underlying cause of post-surgical delayed graft function (DGF), acute kidney injury (AKI), graft rejection, chronic rejection, and chronic graft dysfunction. It can lead to an overwhelming economic burden due to higher length of hospitalization and the eventual need for a more costly option, dialysis. IRI follows a sustained period of ischemic/hypoxic condition and occurs as a consequence of kidney vasculature blood supply restoration, sudden tissue re-oxygenation, and production of toxic substances including reactive oxygen species (ROS) that give rise to oxidative stress, cell death, and tissue damage. There has been significant progress in organ preservation methods to reduce IRI and improve delayed graft function, among which hypothermic machine perfusion (HMP) has been shown to stand out as the method of choice. Recent studies reveal that perfusate solutions supplemented with hydrogen sulfide (H2S) can provide additional cryoprotective benefits and extend the viability of kidneys while improving post-transplantation functional recovery. H2S, a gasotransmitter primarily produced in the vascular endothelial cells, plays an important role in vasorelaxation, angiogenesis, and cytoprotection while it downregulates inflammation, apoptosis, and tissue necrosis. In kidneys, endogenous H2S regulates renal blood flow, glomerular filtration rate, diuresis, natriuresis kaliuresis, blood pressure, oxygen sensing, medullary blood flow, and renin-angiotensin-aldosterone system (RAAS). Preclinical and clinical evidence link low H2S bioavailability to endothelial dysfunction and ischemic-reperfusion injury in kidney transplants. In- vitro and in-vivo studies indicate that supplementing the preservation solution with an H2S donor such as AP39, GYY4137, and NaHS increases epithelial cell viability, improves mitochondrial potency, reduces acute necrosis, and significantly improves ischemia–reperfusion injury. To-date, widespread clinical translation of H2S therapy is hindered by significant concern over safe use and unintended off-target effects of most H2S donors due to a lack of control and knowledge over the dosage during treatment. This leaves a significant opportunity for a disruptive approach for targeted, precision delivery of H2S to facilitate clinical translation of H2S therapy. The proposed Phase I STTR study aims to demonstrate the benefits of a unique electrolytic technology, Genie:S™, for precision delivery of H2S to the perfusate in an HMP kidney preservation system. This collaboration between Exhalix, University of New Mexico School of Medicine, and Texas A&M School of Veterinary Medicine, combines in-depth expertise in device engineering, vascular physiology and surgery, transplant surgery, and animal studies for successfully achieving the proposed aims, and is expected to advance to Phase II effort and beyond for the development of investigational devices for evaluation in preclinical and clinical studies.