Oral Carbon Monoxide Therapeutic to Prevent Vaso-Occlusive Crises in Sickle Cell Disease

 描述(由申请人提供)：拟议项目的总体目标是研究一氧化碳(CO)作为一种新型口服一氧化碳(HBI-002)口服制剂在镰状细胞病(SCD)中作为抗炎剂的潜力。大量的体外和体内研究表明，CO通过抗氧化、抗炎和抗细胞凋亡等过程具有细胞保护作用。研究人员使用四种不同的转基因镰状细胞小鼠模型进行了三项研究，发现血红素加氧酶-1/CO途径在SCD中起关键作用，并证明了极低剂量的CO是限制血管停滞和下调炎症过程的一种新方法。这些研究为一氧化碳在限制SCD发病率方面的潜在有益作用提供了有力的支持。此外，在正常志愿者和使用各种CO传递机制的SCD患者中进行的CO的第一阶段临床研究已经证明了CO的耐受性和安全性，这表明非常低的COHb靶向水平将不会与不良结果相关。HBI-002，一种治疗SCD的口服液制剂正在开发中。HBI-002提供的限定剂量的CO口服给药消除了以前研究的吸入或载体金属CO给药相关的问题，使必要的慢性、安全、无毒的门诊CO剂量成为可能。HBI-002在专有辅料的水基溶液中包含一氧化碳，以最大限度地提高一氧化碳含量。已经演示了HBI-002的概念验证制造。在大鼠和两名成年健康志愿者身上的药代动力学和药效学研究已经证明了概念验证的可行性、耐受性和生物利用度。开发的下一步是证明从HBI-002释放的CO在适当的SCD动物模型中改善结果，并确定SCD小鼠的最小有效剂量，以便在计划的临床试验中提供剂量信息。

 DESCRIPTION (provided by applicant): The overall objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide (CO) as an anti-inflammatory agent in Sickle Cell Disease (SCD) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti-oxidant, anti-inflammatory and anti-apoptotic processes. Researchers found in three studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD and demonstrated that very low doses of CO are a novel approach to limiting vascular stasis and down-regulating the inflammatory process. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. Moreover, Phase 1 clinical studies of CO in both normal volunteers and SCD patients using a variety of CO delivery mechanisms have demonstrated the tolerability and safety of CO, suggesting that the very low targeted levels of COHb will not be associated with adverse outcomes. HBI-002, an oral liquid formulation, is being developed for the treatment of SCD. The oral administration of a defined dose of CO delivered by HBI-002 obviates the problems associated with previously studied inhaled or carrier-metal CO administration, enabling the potential for the necessary chronic, safe, non-toxic outpatient dosing of CO. HBI-002 comprises CO in a water-based solution of proprietary excipients to maximize CO content. Proof-of-concept manufacture of HBI-002 has been demonstrated. Pharmacokinetic and pharmacodynamic studies in rats and in two adult healthy volunteers have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that CO delivered from HBI-002 improves outcomes in an appropriate SCD animal model and to determine the minimum effective dose in SCD mice to inform dosing in planned clinical trials.