Improving Kidney Transplant Outcome with a Novel Complement Inhibitor

DESCRIPTION (provided by applicant): For the greater than 100,000 Americans who suffer from kidney failure each year, transplantation is their best treatment option. Due to the limited availability of suitable donor organs, strategies to expand the available donor pool of kidneys (using "expanded-criteria" donors) and development of approaches to improve successful engraftment are needed. Delayed Graft Function (DGF) is a form of acute kidney failure that occurs in up to 50% of transplants and relates directly to graft performance and patient outcome. DGF is defined as having to use dialysis to keep the patient alive within one week of the transplant surgery. Commonly used immuno-suppressants that are required for long term graft survival are nephrotoxic and actually exacerbate DGF, underscoring the need for a new approach. A major cause of DGF is ischemia-reperfusion injury that results in an inflammatory response that can effect the kidney's ability to function acutely and can also help initiate a cellular immune response that can cause chronic rejection. An important component of ischemia-reperfusion injury is complement activation and in particular C5 activation, leading to C5a and C5b-9 production. C5a and C5b-9 both help orchestrate inflammatory responses that are associated with ischemia reperfusion injuries and delayed graft function, including cytokine and oxygen radical production, white blood cell accumulation and apoptosis. Innate Biotech has developed specific, highly active peptides that inhibit C5 activation and has shown that these peptides limit C5a-mediated cytokine production and the killing of renal cells by C5b-9 in vitro. The studies outlined in this proposal will demonstrate that these peptides will inhibit complement in vivo and in turn will limit the inflammatory response in a porcine ischemia-reperfusion injury model. The project goals include defining the dose-response characteristics of the peptide in vivo, and demonstrating the anti-inflammatory activity by measuring complement activation indices, cytokine levels and the extent of white blood cell infiltration in an ischemic-reperfused kidney. The results of these studies will permit further development of these peptides for use in the renal transplant setting to improve short and long-term graft function. This may also permit the use of kidneys that are currently discarded, extending this preferred modality to a greater percentage of the End Stage Renal Disease patient population (currently 28% of the 100,000 End Stage Renal Disase patients/year). Eventually, this therapeutic could also be used to treat acute and chronic humoral rejection, glomerulonephritis and other autoimmune diseases.