Enhanced Propagation of Adult Human Renal Epithelial Cells Allowing for Commercia

描述（由申请人提供）：肾细胞疗法有望改善急性肾功能衰竭（ARF）、急性肾小管坏死（ATN）、多器官衰竭（MOF）、败血症、心肾综合征（CRS）和终末期肾病（ESRD）患者的生存和整体健康状况。为此，治疗性生物装置解决肾脏替代疗法中被忽视的生理成分正在迅速发展。将这种创新技术转移到临床环境将需要制造使用大量人类细胞的设备。细胞将使用本提案第一阶段开发的增强繁殖（EP）技术从人类移植废弃物中获得。尽管人体组织的可用性仍然有限，但EP方案的发展极大地增强了肾细胞祖细胞的扩增，消除了细胞可用性作为肾细胞治疗临床应用的限制因素。本提案的总体目标是优化在生物人工肾上皮细胞系统（BRECS）中分离、繁殖、冷冻保存、分化、整合和维持人肾内皮细胞所需的方案。植入EP人肾上皮细胞（HRECs）的装置将用于证明在建立良好的猪脓毒症模型中的有效性。将在体外使用全血生物测定法监测广泛的疗效标记物，并将结果与化脓性猪模型的治疗结果相关。数据将用于制定在EP协议下分离和维持的细胞的释放标准，并满足生物许可申请的效价要求。BRECS治疗的目标初始人群将是脓毒症诱导的全身炎症反应综合征（SIRS）的急性肾衰竭患者。维持设备和体外电路的可行性将在预计的7天临床时间过程中进行验证，以实现该临床目标所需的肾脏支持。成功完成II期申请的数据将用于向美国食品和药物管理局（FDA）提交新药研究（IND），用于I/II期临床试验，评估基于强化传播方案的HREC种子的生物治疗装置的安全性和有效性。

DESCRIPTION (provided by applicant): Renal cell therapy promises to improve the survival and overall health of patients suffering from acute renal failure (ARF), acute tubular necrosis (ATN), multiple organ failure (MOF), sepsis, cardiorenal syndrome (CRS) and end stage renal disease (ESRD). To this end, therapeutic biological devices addressing the neglected physiologic component of renal replacement therapy are rapidly being developed. Transfer of this innovative technology to the clinical setting will require the manufacture of devices using a large number of cells of human origin. Cells will be derived from human transplant discards using enhanced propagation (EP) techniques developed in the Phase 1 component of this proposal. Although the availability of human tissue remains limited, development of the EP protocol has greatly enhanced the amplification of renal cell progenitors, removing cell availability as the limiting factor to the clinical application of renal cell therapy. The overall goal of this proposal is to optimize the protocols necessary for the isolation, propagation, cryopreservation, differentiation, integration and maintenance of human EP cells in a bioartificial renal epithelial cell system (BRECS) with regard to manufacturing. Devices seeded with EP human renal epithelial cells (HRECs) will be used to demonstrate efficacy in a well established porcine model of sepsis. A broad panel of efficacy markers will be monitored in vitro using a whole blood bioassay and results correlated with therapy outcome in the septic pig model. Data will be used to develop release criteria for cells isolated and maintained under EP protocols relative to efficacy and to satisfy the potency requirement of the Biologic License Application. The targeted initial population for BRECS therapy will be acute renal failure patients with sepsis induced Systemic Inflammatory Response Syndrome (SIRS). The feasibility of maintaining the device and extracorporeal circuit will be demonstrated over the projected 7 day clinical time course of required renal support for this clinical target. Data derived from the successful completion of the Phase II proposal will be used for an Investigational New Drug (IND) submission to the Food and Drug Administration (FDA) for a Phase I/II clinical trial evaluating the safety and efficacy of biotherapeutic devices seeded with HREC derived from enhanced propagation protocols. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to develop and optimize the generation and qualification of enhanced propagation (EP) protocols for the isolation, expansion and maintenance of human renal epithelial cells (HREC) for use in biologic applications, thus eliminating the issue of limited tissue/cell sources for generation of HRECs. The specific application targeted in this research proposal is for the assessment of utilization of EP HRECs in a bioartificial renal epithelial cell system (BRECS) that effectively adds therapeutic value to a variety of disease processes, including the treatment of Systemic Inflammatory Response Syndrome (SIRS) and sepsis. Severe sepsis with SIRS occurs in 200,000 patients annually in the U.S. and has a mortality rate of 30-40%, even with use of intensive care units and broad spectrum antibiotics. Successful completion of the planned studies in this proposal will allow for an unlimited cell source for use in the BRECS application. This device would greatly reduce the multiorgan effects of sepsis and SIRS, thus improving the clinical outcome of patients affected by these disease processes.