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Principal Investigator: Byoung Chol Oh
Organization: EXPANSE BIO LLC
Fiscal Year: 2024
Award: $897,968
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
The kidney transplant waitlist comprises 83% of the U.S. organ transplant waitlist. Yet, for every 5 patients who die
or become too sick for transplantation, 3 kidneys are discarded. Organ preservation quality is linked to graft lifespan
with kidneys having only 50% graft survival after 10 years. Extending preservation to a week, or longer, would enable
nationwide (theoretically global) donor-recipient matching, allowing many good quality kidneys not transplanted today
(e.g., extended criteria donor kidneys) to be offered to the patients who most need them. Kidney preservation times
of 7-9 days would enable translation of clinical immune tolerance induction, and avoidance of life-long
immunosuppression requirements, from contexts of living donor transplantation to deceased organ donation
(80% of all transplants), improving the lives of transplant recipients, and saving the healthcare system ~ $100 million
dollars each year. Improved and extended preservation technology, with off-the-shelf availability, can enhance
screening for transmissible diseases/malignancies, allow assessment of organ quality, drug/gene therapies for graft
function augmenting, and support xeno-transplantation research. Moreover, 3D slices from preserved kidneys
unmatched for transplant, have wide applicability in drug safety/efficacy testing, and a large variety of research topics.
Building on the project's Phase I feasibility success that demonstrated unprecedented (rabbit) kidney
preservation for up to 14 days, we here scale-up this new technology to develop a (i) nature-inspired and
(ii) machine perfusion enabled, subzero solution to dramatically extend preservation times of human and
porcine (xeno) kidneys. High subzero temperatures (-12 to -20°C) applied using an ultra-stable equilibrium
approach are combined with stress tolerance enhancement and metabolic suppression strategies. Optimized
machine perfusion protocols, 3D combinatorial high throughput screening with precision cut kidney slices,
advanced µCT imaging, whole human kidney, and porcine survival auto transplantation models are employed.
Based upon the significant Phase I achievements and our team's organ preservation experience, we develop
technologies and strategies in Phase II for enhanced human kidney equilibrium ice-free high subzero banking
via: 1) multi-temperature multi-step machine perfusion platform supportive of pre-conditioning protocols, for clinical
scale kidney effective and uniform permeation, at all renal compartmental levels, with (i) biocompatible cryostasis
cocktails formulated on the basis of toxicity neutralization and mutual dilution principles, and (ii) effective
revival/reconditioning protocols for enhanced reperfusion; 2) validation of (168-216h) 7-9 days preservation in
complete absence of ice with (iii) cross country shipping of stored kidneys, and clinical practices of ex vivo renal
perfusion; 3) porcine model kidney orthotopic transplantation with long-term survival, with and without “anywhere
in the world” shipping, and 4) randomized physiologic ex vivo assessment trial of 7-9 days stored human kidneys.
This Phase II sets the stage for logistical model of centralized centers of excellence for preservation and
assessment, enabling vastly improved clinical outcomes and patients' access across the country, and world.
Terms: <3-D><3-Dimensional><3D><Achievement><Achievement Attainment><Address><Animals><Antiheparin Factor><Autograft><Autologous Transplantation><Autotransplant><Blood Platelet Factor IV><Blood platelet factor 4><Body Tissues><Cancers><Chemokine (C-X-C motif) Ligand 4><Clinical><Common Rat Strains><Country><Cryofixation><Cryopreservation><DNA Therapy><Disease><Disorder><Domestic Rabbit><Donor person><Drugs><Equilibrium><Equity><Factor 4><Family suidae><Gene Transfer Clinical><Generations><Genetic Intervention><Goals><Graft Rejection><Graft Survival><Grafting Procedure><Health Care Systems><Healthcare Systems><Heparin Neutralizing Protein><Heterograft><Heterologous Transplantation><High Throughput Assay><Human><Ice><Image><Imaging technology><Immune Tolerance><Immunologic Tolerance><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Incidence><Inequity><Inferior><Kidney><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Lead><Letters><Link><Liver><Living Donors><Logistics><Malignant Neoplasms><Malignant Tumor><Marketing><Medication><Metabolic><Modeling><Modern Man><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Nature><Operative Procedures><Operative Surgical Procedures><Organ><Organ Donations><Organ Donor><Organ Preservation><Organ Transplantation><Organ Transplants><Organ Viability><Oryctolagus cuniculus><Outcome><PF4 Gene><Patients><Pb element><Perfusion><Pharmaceutical Preparations><Phase><Physiologic><Physiological><Pigs><Platelet Factor 4><Play><Protocol><Protocols documentation><Rabbits><Rabbits Mammals><Randomized><Rat><Rats Mammals><Rattus><Recombinant Platelet Factor 4><Recovery><Renal Grafting><Renal Transplantation><Renal Transplants><Reperfusion Therapy><Research><Role><SCYB4><Schedule><Shipping><Slice><Small Inducible Cytokine B4><Small Inducible Cytokine Subfamily B, Member 4><Suidae><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Swine><System><Techniques><Technology><Temperature><Thermodynamic><Thermodynamics><Time><Tissues><Toxic effect><Toxicities><Transplant Recipients><Transplant Rejection><Transplantation><Transplantation Rejection><Transportation><UNOS><United Network for Organ Sharing><Validation><Waiting Lists><Xenograft><Xenograft procedure><Xenotransplantation><animation><authority><autologous graft><autotransplantation><balance><balance function><biocompatibility><biomaterial compatibility><clinical applicability><clinical application><clinical practice><clinical translation><clinically translatable><cold preservation><cold storage><combinatorial><conditioning><cost><design><designing><drug detection><drug safety><drug testing><drug/agent><efficacy testing><experience><flexibility><flexible><gamma-Thromboglobulin><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><graft function><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><high throughput screening><imaging><immune suppression><immune suppressive activity><immune suppressive function><immune system tolerance><immune unresponsiveness><immunological paralysis><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><kidney preservation><kidney tx><life span><lifespan><liver preservation><malignancy><manufacture><medication safety><metabolic depression><neoplasm/cancer><new approaches><new technology><novel approaches><novel strategies><novel strategy><novel technologies><organ allocation><organ allograft><organ graft><organ xenograft><pharmaceutical safety><phase change><pig model><piglet model><platelet factor IV><porcine><porcine model><preconditioning><preservation><randomisation><randomization><randomly assigned><renal><reperfusion><scale up><screening><screenings><social role><stress tolerance><success><suid><surgery><swine model><three dimensional><transplant><transplant donor><transplant model><transplant patient><validations><waitlist><xeno-transplant><xeno-transplantation>