New approaches to kidney banking through nature-inspired high sub-zero preservation strategies

通过受自然启发的高零度保存策略实现肾银行新方法

• 批准号: 10823132
• 负责人: Gerald Brandacher
• 金额: $ 66.04万
• 依托单位: EXPANSE BIO LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10823132
• 关键词: 3-Dimensional; Achievement; Address; Animals; Authorization documentation; Autologous Transplantation; Clinical; Country; Cryopreservation; Disease; Donor person; Equilibrium; Equity; Family suidae; Generations; Goals; Graft Rejection; Graft Survival; Healthcare Systems; Human; Ice; Image; Imaging technology; Immune Tolerance; Immunosuppression; Incidence; Inequity; Inferior; Kidney; Kidney Transplantation; Lead; Letters; Link; Liver; Living Donors; Logistics; Longevity; Malignant Neoplasms; Marketing; Metabolic; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Operative Surgical Procedures; Organ; Organ Donations; Organ Donor; Organ Preservation; Organ Transplantation; Organ Viability; Oryctolagus cuniculus; Outcome; PF4 Gene; Patients; Perfusion; Pharmaceutical Preparations; Phase; Physiological; Play; Protocols documentation; Randomized; Rattus; Recovery; Reperfusion Therapy; Research; Role; Schedule; Shipping; Slice; Surgeon; System; Techniques; Technology; Temperature; Thermodynamics; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; Transportation; United Network for Organ Sharing; Validation; Waiting Lists; Xenograft procedure; animation; authority; biomaterial compatibility; clinical application; clinical practice; clinical translation; combinatorial; conditioning; cost; design; drug testing; efficacy testing; experience; flexibility; gene therapy; graft function; high throughput screening; improved; kidney preservation; liver preservation; manufacture; medication safety; metabolic depression; new technology; novel strategies; organ allocation; phase change; porcine model; preconditioning; preservation; scale up; screening; stress tolerance; success; transplant model

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.

摘要