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供移植的肾脏来满足一个巨大的未得到满足的医疗需求。对于美国40万名终末期肾病患者来说，身体肾库在过去十年里一直停滞不前。因此，在接下来的十年中，透析人群预计将达到200万名患者，总成本为1万亿美元。我们打算使用BREONICS支持体外氧化代谢的温血出血性代谢支持(EMS)灌流技术(32°C)作为平台，提供Mesoblast，Inc.的S非免疫原间充质前体细胞(MPC)技术，即处于晚期临床试验，以介导热缺血损伤的人肾脏的修复。EMS技术正在等待FDA的批准，将开始肾脏移植的临床试验，与修复缺血受损肾脏的MPCS技术相结合，将使获取身体供者肾脏变得可行，从而显著扩大身体肾移植池。目前，美国从未考虑移植身体肾脏，因为它们被认为损坏太严重。在体外EMS灌流过程中，通过定位受损肾脏内的MPC，修复过程将得到加强。将MPC直接靶向肾脏将导致肾内旁分泌和内分泌效应的浓度高于全身给药产生的稀释效应。MPC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灌流，而配对的人肾将与MPC进行48小时的体外EMS灌流。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丢失/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的最佳MPC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MPC来确定肾实质内的沉积和任何滞留、合成、肾脏损伤/修复的标志和灌注后恢复的MPC的特征，以确定人类肾脏在EMS灌流48小时后的表型和合成功能。对我们的项目具有重要意义的是观察到MPC介导的旁分泌效应在48小时内发生，这一时间段对应于我们建议的48小时的体外EMS灌流。Mesoblast，Inc.是一家上市公司，可以很好地将该项目开发的技术商业化。我们相信，使用MPC治疗的同种异体移植物将获得监管部门的批准，因为MPC不是免疫原性的，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，这种扩大器官捐赠者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.