Development of Cobinamide as a Novel Treatment for Aortic Aneurysms of Marfan Syndrome: Phase I Pharmacokinetic Studies

Cobinamide 作为马凡综合征主动脉瘤的新型治疗方法的开发：I 期药代动力学研究

• 批准号: 10545967
• 负责人: Kenneth Dretchen
• 金额: $ 31.14万
• 依托单位: MESA SCIENCE ASSOCIATES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545967
• 关键词: Abnormal Cell; Acidity; Acute; Affect; Anabolism; Aneurysm; Antidotes; Antioxidants; Aorta; Aortic Aneurysm; Area; Biological Availability; Businesses; California; Cardiovascular Abnormalities; Cessation of life; Cobalamin; Cobalt; Complement; Cyanides; DNA; DNA Sequence Alteration; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Duodenum; Extracellular Matrix; Extracellular Matrix Proteins; Eye Abnormalities; FBN1; Faculty; Family suidae; Formulation; Frequencies; Functional disorder; Funding; Gastric Bypass; Genetic Diseases; Goals; Grant; Half-Life; Histidine; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxocobalamin; Infusion procedures; International; Intramuscular Injections; Intravenous; Lead; Legal patent; Lipids; Marfan Syndrome; Molecular; Mus; Mutate; Mutation; Nitric Oxide; Oral; Oral Administration; Oxidative Stress; Oxygen; Pathologic; Pathology; Patients; Peroxonitrite; Persons; Pharmaceutical Preparations; Phase; Plasma; Poison; Poisoning; Prevalence; Production; Proteins; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Research Personnel; Science; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Spontaneous Rupture; Stomach; Sudden Death; Superoxide Dismutase; Superoxides; Testing; Time; Toxic effect; Toxicology; Universities; Vitamin B 12; Water; absorption; analog; ascending aorta; base; catalase; cobinamide; commercialization; drinking water; experience; improved; member; mimetics; nitrosative stress; novel; oxidation; premature; prevent; skeletal abnormality

Marfan Syndrome (MFS) is a genetic disorder, with a prevalence of ~ 1 in 5,000 people. Aneurysms in the ascending aorta are the most serious manifestation of the disease and can lead to sudden death due to spontaneous rupture. Existing treatments are marginally effective. The aneurysms are due largely to increased oxidative stress in aortic smooth muscle cells from abnormal production of superoxide anion and nitric oxide. Cobinamide is the penultimate precursor in the biosynthesis of cobalamin (vitamin B12) and is a powerful antioxidant, serving as a superoxide dismutase and catalase mimetic and neutralizing nitric oxide and peroxynitrite. We have found that administering cobinamide in the drinking water to mice with a fibrillin-1 mutation analogous to a common mutation in Marfan patients abolished oxidative stress and pathological changes in the aorta, and significantly reduced aortic dilation. Our goal is to develop cobinamide as a novel, disease-modifying treatment that could be used in patients with MFS and other forms of aortic aneurysms associated with oxidative stress. An international patent has been submitted for using cobinamide to treat aortic aneurysms, and Dr. Boss, co-investigator on this application, holds patents for using cobinamide as an antidote against toxic chemicals. In this Phase I SBIR grant, we propose to perform pharmacokinetic (PK) studies in rats after oral administration of cobinamide (Aim I) and to synthesize sufficient non-GMP grade cobinamide for the PK studies (Aim II). We propose four interrelated studies in Aim I. (A) Dose Determination Studies. We will determine the single dose administered by gavage required to achieve the plasma concentration found after administering cobinamide continuously in drinking water to mice. (B) Formulation Selection and Mode of Administration Studies. We will compare four different cobinamide formulations, using the dose found in Aim 1A. We will compare the PK profile between administering the drug by gavage to direct instillation into the duodenum in cannulated rats, since gastric acidity could affect cobinamide absorption. The goal is to find the formulation and administration mode that yield the highest plasma concentration for the longest time. (C) Bioavailability Studies. We will use the optimal formulation and administration mode found in Aim 1B and compare the PK profile to that found after injecting the drug intravenously. (D) Repeated Dose Studies. Using the formulation and administration mode found best in Aim 1B, we will determine the frequency of administration required to maintain a steady-state, target plasma concentration. A subsequent Phase II SBIR grant would consist of synthesizing and formulating GMP-grade cobinamide, and performing GLP-level PK and toxicology studies in rats and pigs. The SBIR studies would complement and be performed simultaneously with efficacy and basic mechanistic studies supported by a five-year R01 grant expected to start 04/01/22. Technical and business assistance is requested to develop a high-level plan describing activities that would lead to FDA approval and commercialization of cobinamide.

Marfan综合征（MFS）是一种遗传疾病，患病率为5,000人。动脉瘤 上升主动脉是该疾病的最严重表现，可能导致由于 自发破裂。现有治疗略有效率。动脉瘤主要是由于增加 主动脉平滑肌细胞中的氧化应激来自异常产生的超氧化物阴离子和一氧化氮。 Cobinamide是钴胺素生物合成（维生素B12）的倒数第二个前体，是一种强大的 抗氧化剂，用作超氧化物歧化酶和过氧化氢酶模仿和中和一氧化氮和中和 过氧亚硝酸盐。我们发现，用纤维蛋白-1突变在饮用水中施用cobinamide 类似于Marfan患者的常见突变，消除了氧化应激和病理变化 主动脉，并显着减少主动脉膨胀。我们的目标是发展为新颖的，疾病改良的新生酰胺 可用于与氧化有关的MFS和其他形式的主动脉瘤患者的治疗 压力。已经提交了一项国际专利，用于使用Cobinamide治疗主动脉瘤，Boss博士， 在此应用中，共同投资者拥有专利，用于使用核酰胺作为对有毒化学物质的解毒剂。 在此阶段I SBIR赠款中，我们建议在口服后大鼠进行药代动力学（PK）研究 给药（AIM I）并合成​​足够的非GMP cobinamide进行PK研究 （AIM II）。我们在目标I中提出了四项相互关联的研究。（a）剂量确定研究。我们将确定 单剂量通过野牛施用，以达到施用后达到血浆浓度 在饮用水中连续到小鼠。 （b）配方选择和给药方式 研究。我们将使用AIM 1A中的剂量比较四种不同的核酰胺制剂。我们将 比较通过毒品施用药物以将PK的概况直接滴入十二指肠 插管大鼠，因为胃酸性可能会影响核酰胺吸收。目标是找到配方和 在最长时间内产生最高血浆浓度的给药模式。 （c）生物利用度研究。 我们将使用在AIM 1B中找到的最佳公式和管理模式，并将PK配置文件与该模式进行比较 在静脉注射药物后发现。 （d）重复剂量研究。使用公式和 在AIM 1B中发现的管理模式最佳，我们将确定维护所需的管理频率 稳态的靶等血浆浓度。 随后的II阶段SBIR赠款将包括合成和制定GMP级Cobinamide， 并在大鼠和猪中进行GLP级PK和毒理学研究。 SBIR研究将补充和 由五年R01赠款支持的功效和基本机理研究同时进行 预计将开始04/01/22。要求技术和业务援助制定高级计划 描述将导致FDA批准和商业化的活动。