Year 4 (NCE)
Our research group has been able to successfully develop induced pluripotent stem cells from patients with arginase deficiency, a poorly treated metabolic disorder of the liver that results in intellectual disabilities. In this disorder, the enzyme argianse is mutated and does not function in a normal process called the urea cycle which handles nitrogen metabolism. An excess of nitrogen in the body (through netabolism, diet, injury, or illness), typically as ammonia, can cause brain injury. We have been able to successfully introduce a normal copy of the arginase gene into induced pluripotent stem cells from the patient-derived cells and then developed them into hepatocyte-like cells. At the same time, we have been utilizing a mouse model of arginase deficiency that was further modified to carry genes that suppress their immune system. We have been able to repopulate the liver of these mice with normal human hepatocytes that has led to correction of the defect related to arginase deficiency. These animals demonstrate almost normal circualting blood levels of arginine and ammonia and have improved handling of nitrogen when it is delivered to the mice as an ammonia injection. At present, the induced pluripotent-derived hepatocytes have not engrafted in these mice,and we are continuing to work on strategies to lead to engraftmentment and thus treatment of this disorder. The ultiamte goal of treatment is to be able to take skin cells from a patient with this disorder, develop them into stem cells, add a corrected copy of the arginase gene, develop these cells into hepatocytes and deliver them to the same patient’s liver to correct the disorder. WIth the data to date we are on our way to achieving this goal.