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

摘要：器官保存仍然是一项艰巨的挑战。器官特异性缺血窗口大4-24小时 限制器官移植领域以挽救生命并在美国造成严格的地理限制 全球范围内。然而，通过在采购时停止缺血损伤，我们可以促进增强的移植物 生存能力，因此患者恢复更快，住院时间大大缩短，医疗保健大大减少 增加可供移植的器官数量的成本--所有这些都是在应对最大的挑战的同时。 这一直接到第二阶段SBIR建议的目标是建立XT-vivo的临床前使用，用于非 冷冻、零度缺血保存和移植的同种异体肾移植 与静态冷藏相比，使CIT大大延长，最高可达120小时 储存和运输方式。减少长期缺血期间的损害对肾脏至关重要 移植。事实上，FDA已经承认这项技术是长达120小时的突破性设备 肾脏的保存，这可能导致肾移植的动态转移到后勤。 该项目将组织和器官保存方面的新化学和专业知识与世界领先的 移植。我们将应用新型低温保护剂进行深低温缺血保存。 为显著延长缺血窗口，猪肾脏随后进行了移植 临床相关模型中人体大小的器官。对可能转变的创新模式的评估 目前的保存策略需要使用翻译动物模型来可靠地评估组织 保存后的存活和功能恢复情况。在此，我们提出了拟议工作的两个主要目标。 将合成先进的冷冻保护剂，并将其配制成器官保存溶液。 新型冷冻保护剂将首先应用于猪肾脏的体外保存，在零度以下。 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 进一步评估先在体外极大延长肾脏低温缺血时间至120小时的能力，然后 使用被广泛接受的临床前大型动物移植模型与人类密切相关。 在大大延长了SLA定义的缺血存储后，将对异位肾移植进行研究 迷你猪。动物存活率和肾功能将以类似的方式进行评估，但会更加详细。 在术后第0、1、7和30天评估中期和长期肾功能。 实现所宣布的目标可能会导致器官移植领域的根本改善，并 将有助于获得在批准和临床商业化之前所需的最终数据集。该产品 将延长缺血窗口，简化使用，最大限度地减少对当前实践的干扰，并且功能强大 与目前市场上正在开发的先进器官灌流系统相比，该系统具有成本竞争力。

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.