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.

马凡综合征(MFS)是一种遗传性疾病，患病率为每5000人中有1人。脑部的动脉瘤 升主动脉是该病最严重的表现，可因以下原因导致猝死 自发性破裂。现有的治疗方法略微有效。动脉瘤在很大程度上是由于 超氧阴离子和一氧化氮异常产生引起的主动脉平滑肌细胞氧化应激。 钴酰胺是钴胺(维生素B12)生物合成的倒数第二个前体，是一种强大的 抗氧化剂，作为一种超氧化物歧化酶和过氧化氢酶模拟和中和一氧化氮和 过氧亚硝酸盐。我们已经发现，在饮用水中给予携带纤维蛋白-1突变的小鼠可比胺 类似于马凡患者的一种常见突变，消除了氧化应激和细胞的病理变化 并显著降低了主动脉的扩张。我们的目标是开发可比胺作为一种新型的疾病改良剂 可用于MFS和其他形式的与氧化相关的主动脉瘤患者的治疗 压力。一项使用可比胺治疗主动脉瘤的国际专利已经提交，博斯博士， 这项申请的联合研究员，拥有将可比酰胺用作有毒化学物质解毒剂的专利。 在这一阶段的SBIR赠款中，我们建议在大鼠口服后进行药代动力学(PK)研究 给药(目标I)并为PK研究合成足够的非GMP级的可比酰胺 (目标II)。我们在AIM I(A)剂量决定研究中提出了四项相互关联的研究。我们将确定 单次灌胃给药需要达到给药后的血药浓度 连续给小鼠饮水中的可比胺。(B)提法选择和管理方式 研究。我们将使用目标1A中发现的剂量来比较四种不同的可比胺配方。我们会 大鼠十二指肠直接滴注与灌胃给药的PK谱比较 去势大鼠，因为胃酸会影响可比胺的吸收。我们的目标是找到公式和 最长时间内产生最高血药浓度的给药模式。(C)生物利用度研究。 我们将使用目标1B中找到的最佳配方和管理模式，并将PK配置文件与 在静脉注射毒品后发现的。(D)重复剂量研究。使用该配方和 在目标1B中找到最好的管理模式，我们将确定需要维持的管理频率 一个稳定状态的目标血浆浓度。 随后的第二阶段SBIR赠款将包括合成和配制GMP级可比酰胺， 并在大鼠和猪身上进行GLP水平的PK和毒理学研究。SBIR研究将补充和 与药效研究和基础机制研究同时进行，由五年期R01拨款支持 预计从04/01/22开始。要求技术和商业援助以制定一项高级别计划 描述将导致FDA批准可比胺并将其商业化的活动。