HBI-002 to Treat Parkinson’s Disease

HBI-002 治疗帕金森病

基本信息

批准号：
10490383
负责人：
Edward Gomperts
金额：
$ 18.08万
依托单位：
HILLHURST BIOPHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490383
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

项目摘要

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.

项目摘要拟议项目的目的是评估HBI-002的潜力，这是一种新型的口服碳公式一氧化碳（CO），是帕金森氏病（PD）的神经保护剂。越来越多的研究表明低剂量的CO-和产生内源性CO-的血红素加氧酶（HO）酶预防PD中的神经元细胞丧失，流行病学研究已将吸烟与A相关较低的PD风险。总之，这些观察结果表明，低剂量的CO可能在PD中具有神经保护作用。尼古丁似乎并不是烟草受保护作用的基础，因为PD中尼古丁的临床研究没有显示出明显的改善。在低水平（<10％的共生球蛋白[COHB]）中，例如吸烟者中发现 CO已被证明具有明显的抗凋亡，抗氧化剂和抗炎特性，并且具有成为多种神经系统和非神学疾病的有前途的疗法。 Co是由血红素加氧酶1（HO-1）和2（HO-2）产生，它们将有毒物种血红素转化为CO， biliverdin和铁。融合证据将HO-1和HO-2的功能与PD中的神经保护联系起来，文献表明CO在PD模型中受到保护。在25阶段1中，CO在高达13.9％的COHB水平上的临床安全性和耐受性已被证明和2阶段临床试验（不在PD中，而是在蛛网膜下腔出血中包括）给药，并且正在进行的临床研究与CO。文献中已经很好地证明了水平，为COHB级别提供了支持性的安全数据考虑PD。但是，具有先前治疗行政的CO的长期剂量障碍方法阻止了与PD中的CO治疗开发用于长期使用。 HBI-002是一种新型的口服CO药物，正在开发用于PD的治疗。管理由HBI-002口服给药的CO的定义剂量使CO进一步发展为A 治疗性的同时消除了与先前研究的CO管理策略相关的问题，包括继承的CO，由于需要压缩的CO气缸和对载体分子的毒理学问题（CORMS）暗示剂量，以及载体分子的毒理学问题。具有口服HBI-002的小鼠，大鼠，猪和狗的药代动力学和药效学研究表现出概念验证的可行性，耐受性和生物利用度。开发的下一步该提案中提出的是确认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的效率在两个不同物种中的多个体内PD模型中。在这些模型中，我们将评估HBI-002纹状体营救多巴胺损失，黑质尼格拉多巴胺细胞损失和运动撞击；我们将探索 HBI-002在炎症性级联反应，NRF-2和HO-1途径以及线粒体生物发生上。