This application is focused on preventing adverse events associated with chronic peritoneal dialysis (PD), a renal replacement therapy for end stage renal disease (ESRD). PD as a renal replacement therapy is the method of choice for about 10% of dialysis patients in the US (approximately 26,000 patients) and a greater percentage worldwide. For appropriate patients, peritoneal dialysis can offer some significant advantages as compared to hemodialysis. Most importantly, PD can be performed in the home by the patient without the need to spend several sessions per week in a hemodialysis center. Continuous ambulatory PD allows some patients to receive dialysis while working and pursing other daily activities. In these ways PD can offer enhanced quality of life and independence to patients suffering with ESRD. Loss of peritoneal function is a major factor leading to treatment failure in peritoneal dialysis. The peritoneal membrane undergoes various structural and functional changes with time on dialysis. These alterations include loss of a protective cell layer, deposition of collagen and extracelluar matrix components (fibrosis), and an increase in the number of blood vessels. These changes result in decreased efficiency of PD ultimately requiring discontinuation with the need to substitute another form of renal replacement therapy. The molecular mechanisms that underlie these processes are beginning to be elucidated. High glucose and acidic conditions in the PD fluid cause oxidative stress that can affect membrane integrity of protective cell layer and activate a specific cell signaling pathway, the p38 mitogen-activated protein kinase (MAPK) pathway, that has been shown to lead to expression of a growth factor that stimulates the production of the types of collagen and fibronectin associated with fibrosis. Phrixus believes that Poloxamer-188 (P-188), a novel biological membrane sealant, will be effective in treating peritoneal fibrosis because P-188 has been shown to restore membrane integrity and inhibit the p38 MAPK pathway in other model systems. The first 2 specific aims propose to determine if P-188 can inhibit p38 MAPK activation in cells from the protective layer and to determine if high glucose decreases membrane integrity in these cells from the protective layer and if P-188 can seal any membrane tears. If P-188 works in one of these experiments, then it will be tested in a rat model of PD over a 4-week period to determine if it can prevent fibrosis and growth of new blood vessels in the rat. The long-term goal of the company in the PD arena is to develop Poloxamer-188 (P-188) as an additive to peritoneal dialysis solutions that will prevent and repair damage to the peritoneal membrane and maintain ultrafiltration capacity. Initial work would be supported by this SBIR application while final commercialization will be supported by venture capital investment. Project Narrative. Poloxamer-188 (P-188), a novel biological membrane sealant, is being examined for use in the prevention and treatment of peritoneal fibrosis associated with peritoneal dialysis technique failure which affects hundreds of thousands of patients worldwide. The proposed studies will demonstrate the effect of P-188 on the cell signaling pathways that control the fibrosis, will demonstrate the role of membrane integrity in preventing fibrosis, in cell culture experiments and then confirm that these effects results in preservation of peritoneal membrane integrity in dialyzed rats. Successful completion of these studies will lead to a full clinical development program for the use of P-188 in peritoneal fibrosis prevention.
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