Research Project
7850079
DESCRIPTION (provided by applicant): Available therapies for renal failure continue to be suboptimal with associated mortality rates of over 50% for acute renal failure (ARF) and a life expectancy for end stage renal disease (ESRD) of only 4-5 years. Current renal replacement therapies are non-physiologic, replacing only the filtrative component with no regard to the homeostatic, regulatory, metabolic and endocrine functions of the kidney. To address the need for more advanced therapies, extracorporeal devices containing porcine renal epithelial cells (REC) have been produced and proven to be efficacious in pre-clinical large animal models of sepsis and ARF. A hollow fiber based renal assist device (RAD) containing human cells has been evaluated in FDA-approved Phase I/II and Phase II clinical trials. Currently, biotherapeutic renal devices are in development to ameliorate the effects of ARF, acute tubular necrosis (ATN), multiple organ failure (MOF), sepsis and cardiorenal syndrome (CRS). More specifically, wearable bioartificial kidneys (WEBAK) are being developed for ESRD. The transition of this innovative technology from large animals to the clinical setting will require functional human REC to be generated not only in a manner suitable for device manufacture but in sufficient quantities to treat all patient populations who stand to benefit from renal replacement therapy. ESRD alone currently effects over 430,000 U.S. patients and has an annual cost of more than 25 billion dollars with ESRD patient numbers expected to increase to 2.24 million by 2030. Sepsis leads to ARF, ATN or MOF affecting 700,000 patients annually and currently 350,000 patients suffer from CRS. This research proposal covers enhanced methods for the isolation of REC progenitor cell populations from human cadaver kidneys and propagation to a much larger biomass than current protocols, followed by terminal differentiation to functional REC. Human REC obtained in this manner will be compared to traditionally isolated cells for yield, in-vitro morphology and therapeutic potential. Cell yield per donor will be equated with projected need and technical feasibility of manufacture will be clearly demonstrated by the construction of a WEBAK device using cryopreserved human REC progenitors. Successful application of enhanced propagation techniques to human REC will provide the biomass for the manufacture of a significantly larger number of biotherapeutic devices for treatment of ARF, ATN, MOF, sepsis, CRS and ESRD, all diseases with multibillion dollar markets and, as result, will help save thousands, if not hundreds of thousands, of lives. PUBLIC HEALTH RELEVANCE Transition of renal cell therapy to the clinical setting will require the manufacture of bioengineered devices containing cells of human origin. Currently, the availability of human tissue is limited. Therefore, the amplification and characterization of renal epithelial cells from available human kidney transplant discards must be optimized and therapeutic potential evaluated in the context of whether or not devices can be made in sufficient numbers to effectively treat the burgeoning number of patients suffering from both chronic and acute renal diseases.
