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: 10018537
• 负责人: Gautam Sudhir Ghatnekar
• 金额: $ 30万
• 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 2021-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018537
• 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 严重缺乏可用的捐赠器官，迫使人们利用低质量的肾脏来挽救生命。 病人的生命。在扩大捐助者标准的同时，人们越来越认识到， 器官捐赠、获取和储存对移植后的结果有很大影响。不像心脏 在移植中，肾脏供体可以来自各种来源，包括活体供体、移植后的供体、移植后的供体和移植后的供体。 脑死亡和心脏死亡后的捐赠。然而，绝大多数肾脏都是由死者捐赠的。 供体和脑死亡或心脏死亡后的供体易导致移植后结果较差。 器官移植固有的问题，如局部缺血和长期冷藏，也会对器官移植产生负面影响。 对捐献者的肾脏造成无法弥补的损伤已知这些有害事件会引起内皮细胞 (EC)在植入后由于局部缺血而进一步恶化的功能障碍、炎症和器官损伤 再灌注损伤（IRI），同时也引发供体器官的同种免疫识别。冷藏时 通过减缓新陈代谢， 死亡，目前的制剂不能使与冷藏或缺血再灌注相关的器官损伤最小化 损伤血管内皮作为异体移植物和受体之间的动态界面，是移植物的血管内皮细胞。 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。由于间隙和紧密连接 调节EC功能，促进内皮细胞分子和细胞完整性的治疗策略 移植肾损伤和衰竭的机制。FirstString Research Inc.鉴定、表征并临床评估了连接蛋白43的新型肽模拟物， α-连接蛋白羧基末端（aCT 1），在创伤期间稳定EC的差距和紧密连接 愈合过程，导致细胞通讯的协调，抑制炎症反应， 减少免疫细胞浸润和增强再生特性。aCT 1小巧、稳定、可溶的设计 促进直接易位到细胞中用于细胞内药物递送。临床相关的初步研究 肾、心脏和肺移植模型显示，向标准护理器官补充aCT 1 保存溶液稳定细胞连接，以保护EC免受IRI和延长的冷的有害影响 储存时间我们假设冷保存诱导细胞连接损伤，从而导致EC 再灌注时功能障碍、炎症和肾损伤，以及补充 将治疗性aCT 1肽加入标准护理保存溶液中将保存细胞连接，从而 改善肾脏健康和功能，从而获得上级的移植后结果。在这里我们建议 研究离体aCT 1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进行损伤。