HBI-002 to Treat Delayed Graft Function in Kidney Transplant

项目摘要 拟议项目的目标是调查一氧化碳气体发射器的潜力。 (CO)预防肾移植中的移植肾功能延迟(DGF)和慢性移植物肾病(CAN) 使用一种新的CO口服配方(HBI-002)。一系列重要的体外和体内研究， 证明CO具有抗氧化、抗炎、抗细胞凋亡等细胞保护作用 过程，主要通过血红素加氧酶-1(HO-1)/CO途径，其中HO-1将血红素降解为铁， 胆绿素和胆绿素。肾移植和其他实体器官临床前模型的各种研究 移植，提示CO有可能有利地影响DGF和CaN。 我们有在猪和老鼠身上发表的强有力的概念验证数据，这些数据表明吸入一氧化碳对 减少移植后缺血/再灌注损伤(IRI)和DGF，改善肾功能。这些研究 为一氧化碳在肾移植中的潜在有益作用提供有力的支持。 一氧化碳的安全性和耐受性已在四项成功完成的第一阶段研究中得到证明， 使用各种形式的一氧化碳给药的三个第二阶段的一氧化碳研究。CO在低浓度下的无毒性 文献中对碳氧血红蛋白(COHb)的水平进行了很好的定义，提供了支持性的安全数据 对于正在考虑用于肾移植治疗的目标COHb水平。 HBI-002是一种CO的液体配方，正在开发用于预防肾移植中的DGF。这个 通过口服HBI-002给药限定剂量的CO可进一步 开发一氧化碳作为一种治疗方法，同时避免与先前研究的吸入或 静脉注射载体金属一氧化碳，包括环境安全性和剂量(吸入一氧化碳)和 载体分子毒性(载体-金属结合CO)。小鼠体内药代动力学和药效学研究 大鼠已经证明了概念验证的可行性、耐受性和生物利用度。下一步是 发展是确定HBI-002给药的最佳剂量和给药方案以提高 建立合适的肾移植动物模型并更好地理解其潜在机制的结果(S) 对贪污的保护。

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.