Improving marginal allograft outcomes through cell junction stabilization in transplantation

通过移植中的细胞连接稳定性改善边缘同种异体移植结果

• 批准号: 10173120
• 负责人: Christina Grek
• 金额: $ 99.38万
• 依托单位: XEQUEL BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173120
• 关键词: Adverse event; Affect; Age; Allografting; Animal Model; Antibodies; Aorta; Bilateral; Biological; Biopsy; Blood Vessels; Brain; Brain Death; Cadaver; Cardiac Death; Cardiovascular system; Cell Death; Cell physiology; Cells; Cessation of life; Clinical; Clinical Research; Communication; Connexin 43; Connexins; Cryopreservation; Data; Drug Delivery Systems; End stage renal failure; Endothelial Cells; Endothelium; Event; Failure; Family suidae; Formulation; Functional disorder; Gap Junctions; Gene Expression; Gold; Health; Heart Transplantation; Heart-Lung Transplantation; Hour; Human; Incidence; Inflammation; Inflammatory; Inflammatory Response; Infusion Pumps; Injury; Injury to Kidney; Intercellular Junctions; Ischemia; Kidney; Kidney Transplantation; Length; Living Donors; Measures; Metabolism; Modeling; Molecular; Nephrectomy; Operative Surgical Procedures; Organ; Organ Culture Techniques; Organ Donations; Organ Donor; Organ Preservation Solutions; Organ Transplantation; Outcome; Patients; Peptides; Phase; Price; Process; Property; Pulsatile Flow; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Resistance; Risk; Rodent Model; Small Business Innovation Research Grant; Source; Supplementation; System; Therapeutic; Tight Junctions; Time; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Vascular Permeabilities; cell injury; cell type; clinical translation; clinically relevant; delayed graft function; design; functional restoration; graft failure; implantation; improved; indexing; kidney cell; negative affect; novel; novel therapeutics; organ injury; peptidomimetics; post-transplant; pre-clinical; preservation; prevent; programs; regenerative; renal damage; research clinical testing; standard of care; tissue injury; transplant model; wound healing

Project Summary/Abstract: Transplantation is a highly successful therapy for end-stage renal disease but there is a significant shortage of available donor organs that has forced utilization of low-quality kidneys to save patient’s lives. Extending the donor criteria has coincided with a growing appreciate that factors associated with organ donation, procurement and storage greatly affect post-transplantation outcomes. Unlike heart transplantation, kidney donors can be derived from a variety of sources that include living donors, donation after brain death, and donation after cardiac death. However, the vast majority of kidneys are donated from deceased donors and donation after brain death or after cardiac death predispose poorer post-transplantation outcomes. Problems inherent to organ transplantation, such as ischemia and extended cold storage, also negatively affect and cause irreparable damage to the donor kidney. These injurious events are known to elicit endothelial cell (EC) dysfunction, inflammation, and organ injury that are further exacerbated upon implantation by ischemia reperfusion injury (IRI) while also priming the donor organ for alloimmune recognition. While cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation by slowing metabolism to prevent cell death, current formulations do not minimize organ injury associated with cold storage or ischemia reperfusion injury. Vascular endothelum, which serves as a dynamic interface between the allograft and the recipient, is the initial target of the deleterious events that adversely affect graft health and function. Since gap and tight junctions regulate EC functionality, therapeutic strategies that promote the molecular and cellular integrity of endothelium of donor kidneys could preclude the mechanisms responsible for allograft damage and failure. FirstString Research Inc. has identified, characterized, and clinically-evaluated a novel peptide mimetic of connexin43, alpha-Connexin Carboxy-Terminal (aCT1), that stabilizes the gap and tight junctions of ECs during wound healing processes, leading to coordination of cellular communication, dampened inflammatory responses, reduced immune cell infiltrate, and enhanced regenerative properties. aCT1’s small, stable, soluble design facilitates direct translocation into cells for intracellular drug delivery. Preliminary studies in clinically relevant models of kidney, heart, and lung transplantation reveal that aCT1 supplementation to standard-of-care organ preservation solutions stabilizes cellular junctions to protect EC from injurious effects of IRI and extending cold storage time. We hypothesize that cold preservation induces cell junction damage, which leads to EC dysfunction, inflammation, and renal damage upon reperfusion, and that supplementation of the therapeutic aCT1 peptide to standard of care preservation solution will preserve cell junctions, thereby improving renal health and function leading to superior post-transplantation outcomes. Here we propose to investigate the effect of ex vivo aCT1 pretreatment on donor kidney function, inflammatory state, and tissue injury using clinically relevant pig kidney transplantation models and low-quality human kidneys.

项目摘要/摘要：移植是针对末期肾脏疾病的一种非常成功的疗法 是迫使使用低品质儿童的可用捐助组织的大幅度短缺 病人的生活。扩展捐助者标准与越来越多的因素相吻合 器官捐赠，采购和存储会极大地影响移植后结果。不像心 移植，肾脏捐赠者可以来自包括活捐赠者，捐赠之后的各种来源 脑死亡和心脏死亡后捐赠。但是，绝大多数肾脏都是由死者捐赠的 脑死亡或心脏死亡后的捐赠者和捐赠易感性后植入后结果。 遗传到器官移植的问题，例如缺血和延长的冷藏，也会对 并对供体肾脏造成无法弥补的损害。这些有害事件已知会引起内皮细胞 （EC）功能障碍，感染和器官损伤在缺血后进一步加剧 再灌注损伤（IRI），同时还启动供体器官以进行同种免疫识别。同时保存冷 通过减慢新陈代谢以防止细胞，大量准备使用尸体肾脏进行移植 死亡，当前公式不会最大程度地减少与冷藏或缺血再灌注有关的器官损伤 受伤。血管内皮是同种异体移植物与接受者之间的动态接口，是 有害事件的初始目标会对移植的健康和功能产生不利影响。由于差距和紧密连接 调节EC功能，理论策略，这些策略促进了内皮的分子和细胞完整性 供体肾脏可以排除造成同种异体损害和失败的机制。第一串 Research Inc.已确定，表征和临床评估了一种新型的Connexin43的肽， alpha-connexin羧基末端（ACT1），可稳定伤口期间EC的间隙和紧密连接 康复过程，导致细胞交流的协调，该死的炎症反应， 免疫细胞浸润降低，并增强再生性能。 ACT1的小型，稳定，扎实的设计 促进直接易位到细胞中以进行细胞内药物递送。临床相关的初步研究 肾脏，心脏和肺移植的模型表明，ACT1补充对护理标准器官 保存溶液稳定细胞连接，以保护EC免受IRI受伤的影响并延伸寒冷 存储时间。我们假设冷保护会诱导细胞连接损伤，这导致EC 再灌注后功能障碍，注射和肾脏损害，并补充 治疗ACT1肽达到护理标准的保存解决方案将保留细胞连接 改善肾脏健康和功能，从而导致出色的转移后结果。我们在这里提出 研究离体ACT1预处理对供体肾功能，炎症状态和组织的影响 使用临床相关的猪肾移植模型和低质量的人肾脏受伤。