HBI-002 to Treat Parkinson’s Disease

HBI-002 治疗帕金森病

• 批准号: 10253584
• 负责人: Edward Gomperts
• 金额: $ 45.32万
• 依托单位: HILLHURST BIOPHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253584
• 关键词: Animal Model; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Award; Biliverdine; Biogenesis; Biological Availability; Brain; Canis familiaris; Carbon Monoxide; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Chemicals; Chemosensitization; Chronic; Clinical; Clinical Research; Clinical Trials; Corpus striatum structure; DNA Sequence Alteration; Data; Data Set; Development; Disease; Disease model; Dopamine; Dose; Enzymes; Family suidae; Formulation; Gases; Genes; Genetic Diseases; Goals; Heme; Hemoglobin; Hemoglobin concentration result; Hippocampus (Brain); In Vitro; Inflammatory; Inhalation; Inhalation Exposure; Iron; Link; Literature; MPTP model; MPTP mouse; Mediating; Mitochondria; Modeling; Mus; Neurodegenerative Disorders; Neurologic; Neuroprotective Agents; Nicotine; Oral; Oral Administration; Oxygenases; Parkinson Disease; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Preclinical Testing; Property; Purkinje Cells; Rattus; Research; Research Personnel; Risk; Rodent Model; Safety; Seasons; Small Business Innovation Research Grant; Smoker; Stress; Subarachnoid Hemorrhage; Substantia nigra structure; Testing; Therapeutic; Tobacco; Tobacco smoke; Toxic effect; Toxicology; Toxin; Tyrosine 3-Monooxygenase; Up-Regulation; alpha synuclein; brain cell; cigarette smoking; cytokine; disability; dopaminergic neuron; epidemiology study; experience; heme oxygenase-1; heme oxygenase-2; improved; improved outcome; in vivo; innovation; motor impairment; mouse model; nervous system disorder; neuron loss; neuroprotection; novel; overexpression; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical safety; prevent; protective effect; response; therapeutic development; treatment strategy; volunteer

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.

项目摘要 该项目的目的是评估HBI-002的潜力，HBI-002是一种新型的口服碳制剂， 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 表明，低剂量的CO -和血红素加氧酶（HO），产生内源性CO - 预防帕金森病中神经元细胞的丢失，流行病学研究将吸烟与帕金森病的发病率联系起来。 降低PD风险。总之，这些观察结果表明，低剂量的CO可能对PD具有神经保护作用。 尼古丁似乎并不像尼古丁在帕金森病中的临床研究那样是烟草保护作用的基础 没有明显改善。在低水平（<10%的一氧化碳血红蛋白[COHb]），如吸烟者， CO已被证明具有显著的抗凋亡、抗氧化和抗炎特性，并且它具有 成为多种神经系统和非神经系统疾病的有前途的治疗研究。CO是 由血红素加氧酶1（HO-1）和2（HO-2）产生，它们将有毒物质血红素转化为CO， 胆绿素和铁。越来越多的证据将HO-1和HO-2的功能与PD的神经保护联系起来， 文献表明CO在PD模型中是保护性的。 在25例1期研究中，已证实了高达13.9%COHb水平的CO的临床安全性和耐受性 和使用各种形式的CO的II期临床试验（不用于PD，但包括蛛网膜下腔出血） 在低COHb下不存在CO的毒性， 在文献中已充分证明，为COHb水平提供了支持性安全性数据， 考虑PD。然而，既往治疗性给药的慢性CO给药的障碍 这些方法已经阻止了用于长期使用的CO治疗剂的开发，如在PD中的情况。 HBI-002是一种新型口服CO制剂，正在开发用于治疗PD。投与 通过口服施用HBI-002递送的限定剂量的CO使得能够进一步发展CO作为 治疗性的同时避免了与先前研究的CO给药策略相关的问题， 对于吸入的CO，包括由于需要压缩的CO气瓶而导致的意外吸入暴露， 不精确的剂量，以及对于载体分子结合的CO（CORM），与载体分子有关的毒理学问题。 在小鼠、大鼠、猪和犬中口服HBI-002的药代动力学和药效学研究表明， 证明了概念验证的可行性、耐受性和生物利用度。下一步的发展，如 本提案中提出的目的是证实HBI-002在PD动物模型中的神经保护潜力， 更好地了解神经保护的机制。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对纹状体的拯救。 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对炎症级联、Nrf-2和HO-1通路以及线粒体生物发生的影响。