HBI to Treat Delayed Graft Function in Kidney Transplant

Project Summary The objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide CO to prevent delayed graft function DGF and chronic allograft nephropathy CAN in kidney transplant using a novel oral formulation of CO HBI A significant series of studies both in vitro and in vivo demonstrate that CO has cytoprotective properties through anti oxidant anti inflammatory and anti apoptotic processes primarily through the heme oxygenase HO CO pathway where HO degrades heme into iron biliverdin and CO A variety of studies in preclinical models of kidney transplant and other solid organ transplant suggest the potential of CO to favorably affect the DGF and CAN We have strong published proof of concept data in pigs and rats that inhaled CO offers a substantial benefit to reduce ischemia reperfusion injury IRI and DGF and improve renal function post transplant These studies provide compelling support for a potential beneficial role of CO in kidney transplant The safety and tolerability of CO has been demonstrated in four successfully completed Phase studies and three Phase studies of CO using a variety of forms of CO administration The absence of toxicity of CO at low levels of carboxy hemoglobin COHb has been well defined in the literature providing supportive safety data for the targeted COHb levels being considered for the treatment of kidney transplant HBI a liquid formulation of CO is being developed for the prevention of DGF in kidney transplant The administration of a defined dose of CO delivered by oral administration of HBI enables the further development of CO as a therapeutic while obviating the problems associated with previously studied inhaled or intravenously administered carrier metal CO including environmental safety and dosing inhaled CO and carrier molecule toxicity carrier metal bound CO Pharmacokinetic and pharmacodynamic studies in mice and rats have demonstrated proof of concept feasibility tolerability and bioavailability The next step in development is to determine the optimal dose and dose regimen for HBI administration to improve outcomes in appropriate kidney transplant animal models and to better understand the potential mechanism s of graft protection Project Narrative This proposal is intended to support research evaluating whether HBI an oral carbon monoxide CO therapeutic can improve outcomes in animal models of kidney transplant If successful the project will provide proof of concept for further development of HBI in kidney transplant as a promising therapeutic to improve outcomes from this life saving surgical procedure