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: 10436958
• 负责人: Christina Grek
• 金额: $ 98.75万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436958
• 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：移植是治疗终末期肾病的一种非常成功的疗法，但 可用的供体器官严重短缺，迫使使用低质量的肾脏来挽救生命 延长捐赠者的生命标准与人们对相关因素的日益认识相一致。 与心脏不同，器官捐献、获取和储存极大地影响移植后的结果。 移植时，肾脏捐献者可以有多种来源，包括活体捐献者、术后捐献者 脑死亡和心脏死亡后的捐赠 然而，绝大多数肾脏是死者捐赠的。 脑死亡或心脏死亡后的捐赠者和捐赠容易导致移植后结果较差。 移植器官固有的问题，例如缺血和长期冷藏，也会产生负面影响 已知这些损伤事件会引起内皮细胞的损伤。 (EC) 植入后因缺血而进一步加剧的功能障碍、炎症和器官损伤 再灌注损伤（IRI），同时也在冷保存时启动供体器官的同种免疫识别。 通过减缓新陈代谢以防止细胞死亡，极大地促进了尸体肾移植的使用 死亡，目前的配方不能最大限度地减少与冷藏或缺血再灌注相关的器官损伤 血管内皮是同种异体移植物和受体之间的动态界面。 由于间隙和紧密连接，对移植物健康和功能产生不利影响的有害事件的初始目标。 调节内皮细胞功能、促进内皮分子和细胞完整性的治疗策略 供体肾脏可能会排除导致同种异体移植物损伤和失败的机制。 Research Inc. 已鉴定、表征并临床评估了一种新的 connexin43 肽模拟物， α-连接蛋白羧基末端 (aCT1)，可在伤口过程中稳定 EC 的间隙和紧密连接 愈合过程，导致细胞通讯的协调，抑制炎症反应， 减少免疫细胞浸润，增强 aCT1 的小型、稳定、可溶性设计。 促进直接转位到细胞内进行细胞内药物递送的初步研究。 肾脏、心脏和肺移植模型表明，对标准护理器官补充 aCT1 保存液可稳定细胞连接，保护 EC 免受 IRI 和延长寒冷的伤害性影响 我们追求冷藏会导致细胞连接损伤，从而导致 EC。 再灌注时的功能障碍、炎症和肾损伤，以及补充 将治疗性 aCT1 肽加入标准护理保存液中将保护细胞连接，从而 改善肾脏健康和功能，从而获得更好的移植后结果。 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来损伤。