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.

马凡氏综合症 (MFS) 是一种遗传性疾病，患病率约为五千分之一。动脉瘤位于 升主动脉瘤是该病最严重的表现，可导致猝死 自发破裂。现有的治疗方法效果有限。动脉瘤的发生很大程度上是由于 主动脉平滑肌细胞因超氧阴离子和一氧化氮的异常产生而产生氧化应激。 钴酰胺是钴胺素（维生素 B12）生物合成中的倒数第二个前体，是一种强大的 抗氧化剂，作为超氧化物歧化酶和过氧化氢酶模拟物并中和一氧化氮和 过氧亚硝酸盐。我们发现，在患有 fibrillin-1 突变的小鼠的饮用水中添加可宾酰胺 类似于马凡患者的常见突变消除了氧化应激和病理变化 主动脉，并显着减少主动脉扩张。我们的目标是将可滨酰胺开发为一种新型的疾病缓解药物 可用于 MFS 和与氧化相关的其他形式的主动脉瘤患者的治疗 压力。已提交一项使用可滨酰胺治疗主动脉瘤的国际专利，Boss 博士， 该应用的共同研究员，拥有使用可宾酰胺作为有毒化学品解毒剂的专利。 在此 I 期 SBIR 资助中，我们建议在口服后对大鼠进行药代动力学 (PK) 研究 给予可宾酰胺（目标 I）并合成​​足够的非 GMP 级可宾酰胺用于 PK 研究 （目标二）。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。我们将确定 通过管饲法给予单剂量以达到给药后发现的血浆浓度 将钴酰胺连续添加到小鼠的饮用水中。 (B) 剂型选择和给药方式 研究。我们将使用目标 1A 中的剂量来比较四种不同的可滨酰胺制剂。我们将 比较灌胃给药与直接滴入十二指肠给药之间的 PK 曲线 插管大鼠，因为胃酸会影响可宾酰胺的吸收。目标是找到公式并 最长持续时间产生最高血浆浓度的给药方式。 (C) 生物利用度研究。 我们将使用 Aim 1B 中找到的最佳配方和给药模式，并将 PK 曲线与该模式进行比较 静脉注射药物后发现。 (D) 重复剂量研究。使用配方和 在目标 1B 中发现最佳的给药模式，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 资助将包括合成和配制 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 与五年 R01 资助支持的功效和基本机制研究同时进行 预计于 2022 年 4 月 1 日开始。需要技术和业务援助来制定高级计划 描述了导致 FDA 批准 Cobinamide 和商业化的活动。