Renal Tubules for a Bioartificial Kidney: Monolayer Differentiation of ES Cells

DESCRIPTION (provided by applicant): Over 400,000 people are currently being treated for End-Stage Renal Disease (ESRD) in the United States, with the number of patients expected to grow dramatically over the next two decades. Organ transplantation is the optimal treatment for this disease, but at the current rate of 50,000 transplants per year, this mode of treatment is unable to keep up with the growing number of ESRD cases. The most widely used treatment, hemodialysis, has a significantly increased rate of mortality among ESRD patients when compared to renal transplant patients. To address this gap, an implantable renal assist device is under development; modeled on an extracorporeal device currently in phase II clinical trials. The proposed device will divert the filtrate recovered from a nano-hemofiltration device to the lumen of a high flux device coated with a confluent monolayer of functional renal tubule cells capable of recovering water and other solutes and returning these to the blood. The ideal source of cells for this device will be stem cells derived from each recipient that have been engineered to differentiate into mature renal tubules. To begin to approach this goal, initial effort will be directed toward engineering the well characterized murine embryonic stem cell. Specific aims for this phase I proposal include: 1) Construction of a Odd1 (OSR-1) "knock-in" construct. 2) Isolation of homologously recombined ES cells replacing the Odd1 endogenous locus with the OFP/ODD1 construct. 3) Differentiation of embryonic stem cells toward intermediate mesoderm and its derivatives in monolayer culture. Phase II will exploit these tools to develop a robust stem cell source for testing an implantable renal device. Commercial Applications: This new product will provide an improved treatment for patients with ESRD. It may decrease the mortality rate for patients on hemodialysis and improve the life style of patients by freeing them from periodic dialysis regimens. As of 2002, treatment for this disease accounted for 6.8% of the Medicare budget in the U.S. and currently accounts for over $25 billion dollars of health care cost per year. End Stage renal disease is a large, expensive, and rapidly growing public health problem in the United States. The current treatments include periodic dialysis for the life of the patient or the transplantation of a donor kidney. The creation of an implantable or wearable device employing cells derived from a non-kidney tissue and bioengineered to become kidney cells capable of restoring the metabolic, endocrine, immunologic, and physiological capabilities of a normal kidney has the potential to significantly improve the treatment of this disease.