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.
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.