HBI-002 to Prevent Vaso-Occlusive Crises in Sickle Cell Disease

项目摘要/摘要 拟议项目的目标是评估一氧化碳(CO)气体发射器作为 一种使用新型口服制剂预防镰刀细胞病(SCD)血管闭塞危象(VOCs)的药物 CO(HBI-002)。大量的体外和体内研究表明，一氧化碳具有细胞保护作用 通过抗氧化、消炎和抗细胞凋亡等过程获得多种特性。我们的SBIR第1期支持 研究产生的功效数据与使用四种不同转基因镰刀的四项研究中报告的数据相似 细胞小鼠模型表明，血红素加氧酶-1/CO途径在SCD中起关键作用，表明低剂量的 CO是一种限制血管停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。 一氧化碳的安全性和耐受性已在八个成功完成的第一阶段和第二阶段得到证明 研究，包括两项针对SCD患者的1b期研究，使用各种形式的CO给药。 此外，有10项正在进行的CO临床研究，使用不同形式的CO给药。这个 在文献中已经很好地定义了在低水平的碳氧血红蛋白(COHb)下没有CO的毒性， 为患有HBI-002的SCD患者正在考虑的目标COHb水平提供支持性安全数据。 HBI-002是一种CO的液体配方，正在开发用于预防SCD中的VOCs。政府当局 通过口服HBI-002提供限定剂量的CO能够使CO进一步发展为AS 一种治疗，同时避免了先前研究的吸入或静脉注射相关的问题 管理的载体金属一氧化碳，包括环境安全、剂量和符合慢性 给药(吸入CO)和载体分子毒性、稳定性和生物利用度(载体-金属结合CO)。 口服HBI-002对大鼠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 评估机制、临床前毒理学和临床安全性、耐受性、药代动力学和 HBI-002在镰状细胞病进一步开发中的药效学研究。

PROJECT SUMMARY/ABSTRACT The goal of the proposed project is to evaluate the potential of the gasotransmitter carbon monoxide (CO) as an agent to prevent Vaso-Occlusive Crises (VOCs) 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. Our SBIR Phase 1 supported research has produced efficacy data similar to that reported in four studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD, demonstrating that low doses of CO are a novel approach to limiting vascular stasis and down-regulating inflammatory processes. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. The safety and tolerability of CO has been demonstrated in eight successfully completed Phase 1 and Phase 2 studies, including two Phase 1b studies in SCD patients, using a variety of forms of CO administration. Moreover, there are ten ongoing clinical studies with CO, using various 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 SCD patients with HBI-002. HBI-002, a liquid formulation of CO, is being developed for the prevention of VOCs in SCD. 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, dosing and compliance with chronic administration (inhaled CO) and carrier molecule toxicity, stability, and bioavailability (carrier-metal bound CO). Pharmacokinetic and pharmacodynamic studies in rodents with orally administered HBI-002 have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to evaluate the mechanistic, preclinical toxicologic, and clinical safety, tolerability, pharmacokinetic, and pharmacodynamic profile of HBI-002 for further development in sickle cell disease.