Cell therapy for Repairing Warm Ischemically Damaged Kidneys

描述（由申请人提供）：该项目的目标是通过提供更多用于移植的肾脏来解决大量未满足的医疗需求。在过去的十年里，美国有近40万名终末期肾病患者，尸体肾脏的供应一直停滞不前。因此，在未来十年，透析人口预计将达到200万，总成本将达到1万亿美元。我们打算使用BREONICS支持体外氧化代谢的warm Exsanguinous Metabolic Support （EMS）灌注技术（32°C）作为平台，提供Mesoblast， Inc.的非免疫原性间充质前体细胞（MPCs）技术，该技术处于后期临床试验中，介导热缺血损伤的人体肾脏的修复。EMS技术正在等待FDA批准开始肾移植的临床试验，而MPCs技术用于修复缺血损伤的肾脏，这一技术的结合将极大地扩大尸体肾移植库，使目前在美国从未考虑过移植的尸体供体肾脏成为可能，因为它们被认为受损太严重。在体外EMS灌注过程中，通过将受损肾脏内的MPCs定位，将增强修复过程。与全身给药MPCs的稀释效应相比，MPCs直接靶向肾脏将导致更高的旁分泌和内分泌效应的肾内浓度。MPCs将被荧光标记并在配对的人类肾脏模型中进行测试。将进行一项剂量递增研究，其中一个肾脏将在没有干细胞的情况下进行EMS灌注，而配对的人类肾脏将用MPCs灌注48小时的体外EMS灌注。修复潜力的评估将包括：蛋白尿的程度和可逆性，以确定细胞表面极性的丧失/恢复，肾小球滤过率，DNA合成，细胞骨架再生，趋化因子/细胞因子合成和组织学评估。一旦确定了每克肾脏中MPCs的最佳剂量，我们将进行深入的研究，以更全面地表征人类肾脏的修复过程，使用标记的MPCs来确定肾实质内的沉积和任何保留、合成、肾脏损伤/修复标志物和灌注后恢复的MPCs的特征，以确定48小时EMS灌注后人类肾脏的表型和合成功能。对我们的项目来说，重要的是观察到MPCs介导的旁分泌效应在48小时内发生，这段时间对应于我们建议的48小时体外EMS灌注。Mesoblast公司是一家上市公司，有能力将该项目开发的技术商业化。我们相信用MPCs处理的同种异体移植物将获得监管部门的批准，作为可移植的移植物，因为MPCs不具有免疫原性，不会在体内整合或存活，不会形成畸胎瘤，并且具有既定的安全性。如果成功，这种扩大器官捐献标准的方法将对器官短缺产生积极影响。

DESCRIPTION (provided by applicant): The goal of this project is address a large unmet medical need by providing more kidneys for transplant. For the >400,000 patients with end-stage renal disease in the U.S. the pool of cadaveric kidneys has remained stagnant over the past decade. As a result, the dialysis population is expected to reach >2-million patients in the next decade at an aggregate cost of >$1-trillion USD. We intend to use BREONICS' warm Exsanguinous Metabolic Support (EMS) perfusion technology (32°C) that supports ex vivo oxidative metabolism as the platform to deliver Mesoblast, Inc.'s non-immunogenic mesenchymal precursor cells (MPCs) technology, that is in late Phase clinical trials, to mediate the repair of warm ischemically damaged human kidneys. The combination of EMS technology, that is awaiting FDA approval to begin clinical trials in kidney transplantation, with the MPCs technology to repair ischemically damaged kidneys will provide for significant expansion of the cadaveric renal allograft pool by making it feasible to access cadaveric donors kidneys that today are never considered for transplantation in the U.S. because they are considered to be too damaged. By localizing the MPCs within damaged kidneys during ex vivo EMS perfusion, the repair processes will be potentiated. The targeting of MPCs directly to the kidney will result in higher intrarenal concentrations of the paracrine and endocrine effects than can be achieved with the dilution effects that occur with systemic administration of MPCs. The MPCs will be fluorescently labeled and tested in a paired human kidney model. A dose escalation study will be performed where one kidney will be EMS perfused without stem cells while the paired human kidney will be perfused with the MPCs for 48 hours of ex vivo EMS perfusion. Evaluation of the repair potential will include: the extent and reversibility of proteinuria to identify the loss/recvery of cell surface polarity, glomerular filtration rate, DNA synthesis, cytoskeletal regeneration, chemokine/cytokine synthesis and histologic evaluations. Once the optimized dose of MPCs per gram of kidney is identified, we will perform in- depth studies to more fully characterize the repair processes for the human kidneys using the labeled MPCs to determine deposition and any retention within the renal parenchyma, synthesis, renal markers of injury/repair and characterization of the recovered MPCs following perfusion to determine the phenotype and synthetic functions following the 48 hours of EMS perfusion of the human kidneys. Significant to our project is the observation that MPCs mediated paracrine effects occur within 48 hours, a period that corresponds to our proposed 48 hours of ex vivo EMS perfusion. Mesoblast, Inc. a public company is well positioned to commercialize the technology developed from this project. We believe an allograft treated with MPCs will obtain regulatory approval as transplantable because the MPCs are not immunogenic, do not integrate or survive within the body, do not form teratomas and have an established safety profile. If successful this approach to expanding organ donor criteria will positively impact the organ shortage.