Cell therapy for Repairing Warm Ischemically Damaged Kidneys

细胞疗法修复温暖缺血性损伤的肾脏

基本信息

批准号：
8897995
负责人：
Lauren Brasile
金额：
$ 30万
依托单位：
BREONICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897995
关键词：
Acceleration Address Allografting American Cardiac Death Cardiovascular system Cell Respiration Cell Therapy Cell surface Chronic Clinical Trials DNA biosynthesis Deposition Development Diabetes Mellitus Dialysis procedure Dose End stage renal failure Endocrine Evaluation Family suidae Feasibility Studies Glomerular Filtration Rate Goals Health Hemodialysis Histologic Hour Human Injury Kidney Kidney Transplantation Label Lead Life Mediating Medical Mesenchymal Mesenchymal Stem Cells Metabolic Modeling Musculoskeletal Natural regeneration Nephrons Organ Organ Donations Organ Donor Outcome Patients Perfusion Phase Phase III Clinical Trials Phenotype Population Positioning Attribute Process Proteinuria Recovery Renal Tissue Renal dialysis Renal function Rheumatoid Arthritis Risk Factors Safety Solutions Stem cells Technology Teratoma Testing Time Tissue Engineering Tissues Transplantation base cell injury chemokine commercialization cost cytokine delayed graft function ex vivo perfusion immunogenic injured injury and repair kidney allograft kidney cell kidney repair paracrine patient population phase 2 study precursor cell repaired

项目摘要

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.

描述（由应用程序提供）：通过提供更多的移植肾脏来满足该项目的目标。对于美国，终末期肾脏疾病的患者> 40万名尸体肾脏在过去十年中一直停滞不前。结果，透析人群预计在未来十年内将达到约200万名患者，总费用为1万亿美元。我们打算使用Breonics温暖的新陈代谢支持（EMS）灌注技术（32°C），该技术支持离体氧化代谢作为提供中层中的非免疫性间质质体前体（MPC）技术的平台，在后期的人类临床试验中，在临床临床上进行了调查，该技术是在较晚的临床范围内进行的。 EMS技术的结合，即正在等待FDA批准开始肾脏移植中的临床试验，MPCS技术可以修复缺口损坏的肾脏，可以显着扩大尸体肾脏同种异体移植物，从而使其可用于访问Cadaveric捐赠者的可容易被认为是因为他们被认为是因为他们被认为是因为他们被认为是因为他们被认为是因为他们被认为是因为他们被认为是在美国而被视为太过了。通过在离体EMS灌注过程中，将MPC定位在受损的肾脏中，可以将修复过程进行潜在。直接将MPC靶向肾脏将导致旁分泌和内分泌效果更高的培养基浓度，而对于全身给药MPC的稀释作用而言，可以实现的降低。 MPC将在配对的人肾模型中荧光标记和测试。将进行一项剂量升级研究，其中一个肾脏将在没有干细胞的情况下灌注EMS，而配对的人肾脏将用MPC灌注48小时的EMS EMS灌注。修复潜力的评估将包括：蛋白尿的程度和可逆性确定细胞表面极性的损失/回收，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。一旦确定了每克每克肾脏的MPC的优化剂量，我们将进行深度研究，以更充分地表征人类肾脏的修复过程，使用标记的MPC来确定肾脏paranchyma，合成，肾脏合成，肾脏损伤/修复和表征的肾脏肾脏标记和表征48的肾脏标记和综合的表征和综合的表征，并确定现象的表征和表征，以确定肾脏paranchyma的沉积和任何保留。人类肾脏的灌注。对我们项目的重要意义是观察到MPCS介导的旁分泌作用发生在48小时内，这与我们提出的48小时的离体EMS灌注相对应。 Mesoblast，Inc。一家上市公司可以使该项目开发的技术商业化。我们认为，用MPC处理的同种异体移植物将获得调节批准，因为MPC不是免疫原性，不整合或在体内生存，不要形成畸胎瘤并具有既定的安全性。如果成功扩展器官供体标准的方法将对器官短缺产生积极影响。