HBI-002 to Treat Parkinson’s Disease

项目总结 拟议项目的目标是评估HBI-002的潜力，HBI-002是一种新的碳口服配方 一氧化碳(CO)，作为帕金森病(PD)的神经保护剂。越来越多的研究 提示低剂量的CO-和产生内源性CO-的血红素加氧酶(HO)酶- 防止帕金森病患者神经细胞丢失，流行病学研究已将吸烟与 较低的帕金森病风险。综上所述，这些观察结果表明，低剂量的一氧化碳可能对帕金森病患者具有神经保护作用。 尼古丁似乎不是烟草保护作用的基础，就像帕金森病患者尼古丁的临床研究那样。 没有显示出明显的改善。在低水平(10%一氧化碳血红蛋白[COHb])，如在吸烟者中发现的， 一氧化碳已被证明具有显著的抗细胞凋亡、抗氧化和抗炎特性，而且它具有 成为治疗多种神经系统和非神经系统疾病的有希望的治疗药物。CO是 由血红素加氧酶1(HO-1)和血红素加氧酶2(HO-2)产生，将有毒物种血红素转化为一氧化碳， 胆绿素和铁。越来越多的证据将HO-1和HO-2的功能与帕金森病的神经保护联系起来，并且 文献表明，在PD模型中，CO具有保护性。 COHb含量高达13.9%的CO的临床安全性和耐受性已在25个阶段1中得到证明 和第二阶段临床试验(不是PD，但包括蛛网膜下腔出血)，使用各种形式的CO 给药，有正在进行的CO的临床研究。CO在低COHb条件下的无毒性 水平已经在文献中得到了很好的证明，为下面的COHb水平提供了支持性的安全数据 警局的考虑因素。然而，慢性服用一氧化碳的障碍与先前的治疗管理 方法已经阻止了慢性使用的一氧化碳治疗的发展，就像帕金森病的情况一样。 HBI-002是一种新的口服一氧化碳药物，正在开发中，用于治疗帕金森病。管理一家公司 通过口服HBI-002提供的限定剂量的CO使CO进一步发展为 治疗的同时避免了与先前研究的CO给药策略相关的问题， 包括，对于吸入的一氧化碳，由于需要压缩的一氧化碳钢瓶和 不精确的剂量，以及对于载体分子结合的CO(球茎)，与载体分子有关的毒理学问题。 口服HBI-002的小鼠、大鼠、猪和狗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，如 本提案的目的是证实HBI-002在帕金森病动物模型中的神经保护作用。 更好地理解神经保护的机制。为此，我们将评估HBI-002的疗效 在两个不同物种的多个体内PD模型中。在这些模型中，我们将评估HBI-002对纹状体的挽救 多巴胺丢失、黑质多巴胺细胞丢失和运动障碍；我们将探讨 HBI-002在炎症级联反应、NRF-2和HO-1通路以及线粒体生物发生中的作用。

PROJECT SUMMARY The goal of the proposed project is to evaluate the potential of HBI-002, a novel oral formulation of carbon monoxide (CO), as a neuroprotective agent in Parkinson’s disease (PD). A growing body of research suggests that low doses of CO - and the heme oxygenase (HO) enzymes that generate endogenous CO - protect against neuronal cell loss in PD, and epidemiologic studies have associated cigarette smoking with a lower risk of PD. Together, these observations suggest that low doses of CO may be neuroprotective in PD. Nicotine does not appear to underlie the protective effect of tobacco, as a clinical study of nicotine in PD did not show significant improvement. At low levels (<10% CO-hemoglobin [COHb]), such as found in smokers, CO has been shown to have marked anti-apoptotic, anti-oxidant, and anti-inflammatory properties, and it has become a promising therapeutic under study for multiple neurologic and non-neurologic diseases. CO is generated by heme oxygenase 1 (HO-1) and 2 (HO-2), which transform the toxic species heme into CO, biliverdin, and iron. Converging evidence links the function of HO-1 and HO-2 to neuroprotection in PD, and the literature indicates that CO is protective in a PD model. The clinical safety and tolerability of CO at levels up to 13.9% COHb has been demonstrated in 25 Phase 1 and Phase 2 clinical trials (not in PD, but including in subarachnoid hemorrhage) using a variety of forms of CO administration, and there are ongoing clinical studies with CO. The absence of toxicity of CO at low COHb levels has been well demonstrated in the literature, providing supportive safety data for the COHb levels under consideration for PD. However, barriers to chronic dosing of CO with prior therapeutic administrative approaches have prevented the development of a CO therapeutic for chronic use, as would be the case in PD. HBI-002, a novel oral CO drug product, is being developed for the treatment of PD. The administration of a defined dose of CO delivered by oral administration of HBI-002 enables further development of CO as a therapeutic while obviating the problems associated with previously studied CO administration strategies, including, for inhaled CO, accidental inhalation exposure due to the need for compressed CO cylinders and imprecise dosing, and, for carrier molecule-bound CO (CORMs), toxicological concerns with carrier molecules. Pharmacokinetic and pharmacodynamic studies in mice, rats, pigs, and dogs with oral HBI-002 have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development, as presented in this proposal, is to confirm the neuroprotective potential of HBI-002 in animal models of PD and to better understand the mechanisms of neuroprotection. For this purpose, we will assess the efficacy of HBI-002 in multiple in vivo PD models in two different species. In these models we will assess HBI-002 rescue of striatal dopamine loss, substantia nigra dopamine cell loss, and motor impairment; and we will explore the impact of HBI-002 on inflammatory cascades, Nrf-2 and HO-1 pathways, and mitochondrial biogenesis.