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-002). 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-1 (HO-1)/CO pathway, where HO-1 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 1 studies and three Phase 2 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-002, 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-002 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-002 administration to improve outcomes in appropriate kidney transplant animal models and to better understand the potential mechanism(s) of graft protection.
This proposal is intended to support research evaluating whether HBI-002, 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-002 in kidney transplant as a promising therapeutic to improve outcomes from this life-saving surgical procedure.
| Correa-Costa, Matheus; Gallo, David; Csizmadia, Eva et al. (2018) Carbon monoxide protects the kidney through the central circadian clock and CD39. Proc Natl Acad Sci U S A 115:E2302-E2310 |
| Zheng, Yueqin; Ji, Xingyue; Yu, Bingchen et al. (2018) Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nat Chem : |
