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.

抽象的 然而，每 5 名死亡患者中就有 83% 是肾移植等待名单。 或因病重而无法移植，3 个肾脏被丢弃 器官保存质量与移植物的寿命有关。 10 年后肾脏移植存活率仅为 50%，将保存时间延长至一周或更长时间将能够实现。 全国范围内（理论上是全球范围内）的供体-受体匹配，允许许多目前尚未移植的优质肾脏 （例如，延长标准供体肾脏）提供给最需要肾脏保存时间的患者。 7-9天的时间将能够转化临床免疫耐受诱导，并避免终身免疫耐受。 免疫抑制要求，从活体捐赠者移植到死者器官捐赠的情况 （占所有移植手术的 80%），改善移植受者的生活，并节省医疗保健系统约 1 亿美元 改进和扩展的保存技术以及现成的可用性可以提高每年的成本。 筛查传染性疾病/恶性肿瘤，评估器官​​质量，移植药物/基因治疗 功能增强，并支持异种移植研究。此外，来自保存肾脏的 3D 切片。 对于移植来说是无与伦比的，在药物安全性/功效测试方面具有广泛的适用性，并且研究课题种类繁多。 建立在该项目第一阶段可行性成功的基础上，该成功展示了（兔）肾脏 保存长达 14 天，我们在此扩大这项新技术的规模，以开发 (i) 受自然启发且 (ii) 机器灌注启用的低温解决方案可显着延长人类和动物的保存时间 使用超稳定平衡施加零度以下的高温（-12 至 -20°C）。 方法与应激耐受增强和代谢抑制策略相结合。 机器灌注方案、使用精密切割肾脏切片的 3D 组合高通量筛选、 采用先进的μCT成像、人全肾和猪存活自体移植模型。 基于第一阶段的重大成果和我们团队的器官保存经验，我们开发 第二阶段增强人体肾脏平衡的技术和策略无冰高低温库 通过：1）支持预处理方案的多温度多步骤机器灌注平台，用于临床 在所有肾区室水平上衡量肾有效性和均匀渗透性，并具有 (i) 生物相容性低温 根据毒性中和和相互稀释原理配制的混合物，以及（ii）有效 增强再灌注的复苏/再适应方案；2) 保存 (168-216 小时) 7-9 天的验证 完全没有冰（iii）储存肾脏的跨国运输，以及离体肾的临床实践 3）具有长期存活率的猪模型肾原位移植，有或没有“任何地方” “在世界范围内”运输，以及 4) 对保存 7-9 天的人类肾脏进行随机生理离体评估试验。 第二阶段为集中式卓越中心的后勤模型奠定了基础，以保护和保护 评估，从而大大改善临床结果和患者在全国乃至全世界的访问。