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使用新型CO口服制剂（HBI-002）研究气体递质一氧化碳（CO）作为镰状细胞病（SCD）抗炎剂的潜力。大量的体外和体内研究表明，CO通过抗氧化、抗炎和抗凋亡过程具有细胞保护特性。研究人员在三项使用四种不同转基因镰状细胞小鼠模型的研究中发现，血红素加氧酶-1/CO途径是SCD的关键，并证明极低剂量的CO是限制血管淤滞和下调炎症过程的新方法。这些研究为CO在限制SCD发病率方面的潜在有益作用提供了令人信服的支持。此外，使用各种CO递送机制在正常志愿者和SCD患者中进行的CO的I期临床研究已经证明了CO的耐受性和安全性，表明非常低的COHb目标水平与不良结局无关。HBI-002是一种口服液体制剂，正在开发用于治疗SCD。通过HBI-002递送的限定剂量的CO的口服给药避免了与先前研究的吸入或载体金属CO给药相关的问题，使得能够进行必要的慢性、安全、无毒的门诊CO给药。HBI-002在专有赋形剂的水基溶液中包含CO以使CO含量最大化。HBI-002的概念验证生产已经得到证实。在大鼠和两名成年健康志愿者中进行的药代动力学和药效学研究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递送的CO改善适当SCD动物模型中的结果，并确定SCD小鼠中的最小有效剂量，以告知计划的临床试验中的给药。

 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.