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.

马凡氏综合征（MFS）是一种遗传性疾病，患病率约为1/5000。动脉瘤 升主动脉是该疾病最严重的表现，并可导致猝死， 自发破裂现有的治疗方法效果甚微。动脉瘤主要是由于 超氧阴离子和一氧化氮的异常产生导致主动脉平滑肌细胞的氧化应激。 钴酰胺是钴胺素（维生素B12）生物合成中的倒数第二个前体，并且是一种强有力的维生素B12合成酶。 抗氧化剂，用作超氧化物歧化酶和过氧化氢酶模拟物，中和一氧化氮， 过氧亚硝酸盐。我们已经发现，在饮用水中给予具有β-淀粉样蛋白-1突变的小鼠可宾酰胺， 类似于马凡氏症患者中的常见突变， 主动脉，并显著减少主动脉扩张。我们的目标是开发一种新型的， 可用于MFS和其他形式的氧化相关主动脉瘤患者的治疗 应力一项国际专利已经提交，用于使用cobinamide治疗主动脉瘤，和博士博斯， 该申请的共同研究者，拥有使用cobinamide作为有毒化学品解毒剂的专利。 在第一阶段SBIR补助金中，我们建议在大鼠中进行药物动力学（PK）研究， 给予可宾胺（Aim I），并合成足够的非GMP级可宾胺用于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)剂量测定研究。康贝特人将以 单次灌胃给药，以达到给药后的血药浓度 给小鼠连续饮水。(B)制剂选择和给药方式 问题研究我们将使用目标1A中的剂量比较四种不同的可宾酰胺制剂。我们将 比较了在以下患者中通过灌胃给予药物与直接滴入十二指肠之间的PK特征： 插管大鼠，因为胃酸会影响考比胺的吸收。目标是找到公式， 给药模式可在最长时间内产生最高血浆浓度。(C)生物利用度研究。 我们将使用目标1B中发现的最佳制剂和给药模式，并将PK特征与目标1B中发现的最佳制剂和给药模式进行比较。 是在静脉注射毒品后发现的(D)重复给药研究。使用该制剂和 目标1B中发现的最佳给药模式，我们将确定维持所需的给药频率 稳态目标血浆浓度。 随后的第二阶段SBIR赠款将包括合成和配制GMP级可宾酰胺， 并在大鼠和猪中进行GLP水平的PK和毒理学研究。SBIR研究将补充和 与由五年R 01资助的疗效和基本机制研究同时进行 预计将于2004/01/22开始。请求提供技术和业务援助，以制定一项高级别计划 描述了将导致FDA批准和可宾酰胺商业化的活动。