The World Health Organization estimates that organ transplants are meeting less than 10% of global demand,in part because the short preservation periods possible with current technology limits options for organassessment and sharing. Even potentially functional, transplantable organs may be turned down by onetransplant center after another until its short preservation limit is exceeded. We propose development of a newstasis cocktail, based upon our Unisol⢠solution, optimized for storage of kidneys that would enable crosscontinent organ matching and exchange that in turn would potentially improve the lives of thousands of patientswith end stage renal disease. Our technology improves upon the most tried and true method for hypothermickidney storage in clinical practice that is relatively inexpensive, ice cooled, and easy to ship by air due to no needfor batteries or power supply. In this proposal we will assess optimization of Unisol⢠for hypothermic kidneystorage by supplementation with compounds targeting specific mechanisms of ischemia and reperfusion injuryin five specific aims (SAs). In Phase I controls consisting of exposure to current clinical practice organ storagesolutions will be performed in both SAs. In SA#1 we sequentially test potential formulation supplements in vitroon several human kidney cell types and then the best outcomes in an in vivo rat kidney transplant model. The invitro studies will be performed in our laboratories in South Carolina employing primary human renal epithelialcells and the results will be confirmed using several types of primary human kidney cells. Cell viability assayswill be employed, including alamarBlue, live dead stains, Trypan blue, and the MTT assay, to identify the bestsupplement formulations. In SA#2 in vivo studies to evaluate the best supplement formulations from SA#1 willbe performed at Johns Hopkins in Maryland using an orthotopic rat kidney transplant model under the directionof Professor Gerald Brandacher. Successful demonstration of 100% animal/ kidney survival after 24h and >40%after 36h of storage and 28 days post-transplant will be considered demonstration of feasibility for progressionto Phase II with 3 SAs. In Phase II we will scale up to porcine kidneys ex vivo (SA#3), followed by in vivotransplantation (SA#4) and then ex vivo testing with human kidneys (SA#5). Tissue MALDI, proteomics andproinflammatory cytokines will be also be assessed in SAs 2-5 to provide a better understanding of outcomesand potentially suggest formulation modifications. We will transition from GMP to cGMP Unisol⢠production forPhase II. Larta, Inc., will assist Tissue Testing Technologies LLC in further development of our Phase II businessplans during Phase I and transitioning to the market place in Phase II.
Public Health Relevance Statement: NARRATIVE:
For every 3 kidneys procured from donors that are not used for transplantation 5 patients on the waiting list die.
Many of the unused kidney donations could have been employed for transplantation if more time was available
from the moment of organ procurement to transplant. Kidney transplantation is the preferred treatment to
increase longevity and quality of life for people with end-stage kidney disease, but due to a shortage of
transplantable kidneys, 7 of 10 patients will remain on dialysis and many will die while waiting for a kidney.
There are about 100,000 waiting-list candidates for kidneys at any time but only around 20,000 will receive
transplants each year. Optimization of Unisol⢠employing a mechanistic approach will buy more time from the
moment of organ procurement to transplant and permit better matching over longer distances that will result in
better outcomes.
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