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HBI-002 to Treat Delayed Graft Function in Kidney Transplant

HBI-002 治疗肾移植中移植物功能延迟

基本信息

批准号：
9200049
负责人：
Edward Gomperts
金额：
$ 86.26万
依托单位：
HILLHURST BIOPHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9200049
关键词：
Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptotic Biliverdine Binding Biological Availability Biological Markers Biopsy Specimen Blood Circulation Blood flow Breathing Carbon Monoxide Carboxyhemoglobin Cardiac Death Chronic Chronic rejection of renal transplant Clinical Conscious Data Development Dose Drug Kinetics Family suidae Feasibility Studies Formulation Gene Chips Genes Graft Survival Heart Heme Hemoglobin Hemoglobin concentration result Histopathology Human In Vitro Incidence Institutes Iron Ischemia Kidney Kidney Transplantation Life Literature Liver Lung Magnetic Resonance Imaging Measures Metals Mitochondrial DNA Modality Modeling Mus Operative Surgical Procedures Oral Oral Administration Organ Transplantation Organ failure Outcome Pathway interactions Patients Pharmacodynamics Physicians Physiology Pre-Clinical Model Prevention Process Property Publishing Rattus Regimen Renal function Reperfusion Injury Reperfusion Therapy Research Support Risk Factors Rodent Rodent Model Role Safety Series Severities Small Intestines Solid Source Surgeon Testing Therapeutic Therapeutic Intervention Time Toxic effect Transplant Recipients Transplantation Treatment Protocols Warm Ischemia Work base clinically relevant cost delayed graft function graft function heme oxygenase-1 improved improved outcome in vivo innovation kidney allograft liquid formulation novel phase 1 study phase 2 study prevent protective effect renal ischemia standard measure tissue oxygenation

项目摘要

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-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.

项目总结