Greatly Extended Subzero Ischemic Storage of Renal Allografts Using Novel Bio-inspired Next Generation Cryoprotectants

使用新型仿生下一代冷冻保护剂大大延长肾同种异体移植物的零度以下缺血储存

• 批准号: 10761617
• 负责人: Gerald Brandacher
• 金额: $ 97.12万
• 依托单位: X-THERMA INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761617
• 关键词: Animal Model; Animals; Autologous Transplantation; Back; Biological Markers; Blood Chemical Analysis; Blood donor; Breakthrough device; Chemicals; Chemistry; Clinical; Collaborations; Complete Blood Count; Creatinine; Cryopreservation; Data Set; Dimethyl Sulfoxide; Evaluation; Family suidae; Flushing; Formulation; Funding; Geography; Goals; Health Care Costs; Histology; Human; Immunohistochemistry; Injury; Injury to Kidney; Investigation; Ischemia; Kidney; Kidney Transplantation; Length of Stay; Life; Logistics; Marketing; Methods; Miniature Swine; Modality; Modeling; Monitor; Organ; Organ Preservation; Organ Preservation Solutions; Organ Size; Organ Transplantation; Patient-Focused Outcomes; Patients; Peptoids; Perfusion; Phase; Play; Postoperative Period; Preservation Technique; Process; Production; Property; Proteins; Protocols documentation; Recommendation; Recovery; Recovery of Function; Renal Blood Flow; Renal function; Reperfusion Therapy; Rewarming; Role; Serum; Small Business Innovation Research Grant; Surgeon; System; Technology; Temperature; Testing; Time; Tissue Preservation; Tissue Viability; Toxic effect; Translating; Transplantation; Universities; Urine; Weight; Wisconsin; Work; clinically relevant; commercialization; cost; improved; improved outcome; in vivo; innovation; kidney allograft; kidney preservation; medical schools; next generation; novel; post-transplant; pre-clinical; preservation; success; transplant model

Abstract: Organ preservation remains a daunting challenge. Organ specific ischemia windows of 4-24h greatly limit the field of organ transplantation to save lives and cause severe geographic restriction in the US and globally. However, by halting ischemic damage at the point of procurement, we could facilitate enhanced graft viability and thus faster patient recovery, drastically shorter hospital stays, and greatly diminished healthcare costs – all while tackling the biggest challenge of all – to increase the amount of available organs for transplant. The goal of this Direct-to-PhaseII SBIR proposal is to establish the pre-clinical use of XT-ViVo for the non- frozen, subzero ischemic preservation and transplantation of renal allografts leading to improved outcome in comparison to static cold storage and to render greatly extended CIT of up to 120h possible using practical storage and transport methods. Reducing damage during extended ischemia is of critical relevance to kidney transplantation. Indeed, the FDA has recognized this technology as a Breakthrough Device for up to 120h preservation of the kidney, which could lead to dynamic shifts to logistics of kidney transplantation. This project combines novel chemistry and expertise in tissue and organ preservation with world leaders in transplantation. We will apply novel cryoprotectants to high subzero temperature ischemic preservation of porcine kidneys followed by subsequent transplantation in an effort to significantly extend the ischemia window of human-sized organs in a clinically relevant model. The evaluation of innovative modalities that may transform current preservation strategies requires the use of translational animal models for reliable assessment of tissue viability and functional recovery post-preservation. Herein, we propose two primary aims of the proposed work. Advanced cryoprotectants will be synthesized and prepared into formulations as organ preservation solutions. The novel cryoprotectants will first be applied to the preservation of pig kidneys ex vivo, at subzero temperature. We will assess kidney survival, function, injury biomarkers, histology, and immunohistochemistry. This work will further asses the ability to greatly extend subzero ischemia time of the kidney up to 120h first ex vivo, and then using a widely-accepted preclinical large animal transplantation model for close clinical relevance to humans. Heterotopic kidney transplantation will be investigated after greatly extended ischemic storage on SLA-defined miniature swine. Animal survival and kidney function will be assessed similarly with a heightened level of detail at post-operative day 0, 1, 7, and 30 to assess both intermediate and long-term kidney function. Execution of the stated aims could result in a fundamental improvement in the field of organ transplantation and will aid acquisition of the final data set required prior to clearance and clinical for commercialization. The product will offer extension of the ischemia window, simplified use with minimal disruption of current practice, and strong cost competitiveness compared to the advanced organ perfusion systems being developed in the market today.

翻译后摘要：器官保存仍然是一个艰巨的挑战。器官特异性缺血时间窗4 - 24h， 限制器官移植领域以挽救生命，并在美国造成严重的地理限制， 在全球然而，通过在获取点停止缺血性损伤，我们可以促进增强移植物 生存能力，从而更快的病人恢复，大大缩短住院时间，大大减少医疗保健 成本--同时应对最大的挑战--增加可供移植的器官数量。 本直接进入II期SBIR提案的目标是确定XT-ViVo在非临床研究中的临床前使用。 冷冻、低温缺血保存和移植同种异体肾移植，改善了 与静态冷藏相比，使用实际的冷藏设备， 储存和运输方法。减少长期缺血期间的损伤对肾脏至关重要 移植事实上，FDA已将该技术视为突破性设备长达120小时 肾脏的保存，这可能导致肾脏移植物流的动态转变。 该项目将组织和器官保存方面的新颖化学和专业知识与世界领先的 移植我们将应用新型的冷冻保护剂进行高低温缺血保存， 猪肾，随后进行移植，以显著延长缺血窗口 人体大小的器官在一个临床相关的模型。对可能改变 目前的保存策略需要使用平移动物模型来可靠地评估组织 保存后的活力和功能恢复。在此，我们提出了拟议工作的两个主要目标。 先进的冷冻保护剂将被合成并制成制剂作为器官保存溶液。 新型冷冻保护剂将首先应用于在零度以下温度下离体保存猪肾。 我们将评估肾脏存活率、功能、损伤生物标志物、组织学和免疫组织化学。这项工作将 进一步评估了将肾脏的零下缺血时间大大延长至120小时的能力，首先离体，然后 使用广泛接受的临床前大型动物移植模型，与人类临床密切相关。 将研究在SLA定义的极大延长缺血储存后的异位肾移植。 迷你猪将以类似方式评估动物存活率和肾功能，并提高详细程度 在术后第0、1、7和30天评估中期和长期肾功能。 实现上述目标可能会导致器官移植领域的根本性改善， 将有助于在批准和商业化临床之前获得所需的最终数据集。产品 将提供缺血窗口的扩展，简化使用，最大限度地减少对当前实践的干扰， 与当今市场上正在开发的先进器官灌注系统相比，具有成本竞争力。