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的肾脏用于移植来解决大量未满足的医疗需求。对于美国> 400，000例终末期肾病患者，尸体肾脏的数量在过去十年中一直停滞不前。因此，预计在未来十年内，透析人口将达到200多万患者，总成本超过1万亿美元。我们打算使用BREONICS的温暖的失血代谢支持（EMS）灌注技术（32°C），支持离体氧化代谢作为平台，以提供Mesoblast，Inc.的非免疫原性间充质前体细胞（MPC）技术，这是在后期临床试验，以调解修复热缺血损伤的人肾脏。正在等待FDA批准开始肾移植临床试验的EMS技术与用于修复缺血性损伤的肾的MPC技术的组合将通过使接近尸体供体肾变得可行而提供尸体肾同种异体移植物库的显著扩展，所述尸体供体肾在今天在美国从未被考虑用于移植，因为它们被认为太受损。通过在离体EMS灌注期间将MPC定位在受损的肾脏内，将加强修复过程。MPC直接靶向肾脏将导致肾内旁分泌和内分泌效应浓度高于全身给予MPC时产生的稀释效应。将对MPC进行荧光标记，并在配对人肾模型中进行检测。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灌注，而配对的人肾脏将用MPC灌注48小时的离体EMS灌注。修复潜力的评价将包括：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价。一旦确定了每克肾脏的MPC的最佳剂量，我们将进行深入研究，以使用标记的MPC更全面地表征人肾脏的修复过程，以确定肾实质内的沉积和任何保留，合成，肾损伤标志物/灌注后恢复的MPC的修复和表征，以确定EMS 48小时后的表型和合成功能人体肾脏的灌注。对我们的项目重要的是观察到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提出的48小时离体EMS灌注。中胚层公司一家上市公司完全有能力将该项目开发的技术商业化。我们相信用MPC治疗的同种异体移植物将获得监管机构的批准，因为MPC没有免疫原性，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.