Novel COG Compounds to Treat Asthma

治疗哮喘的新型 COG 化合物

• 批准号: 8314407
• 负责人: MICHAEL PETER VITEK
• 金额: $ 26.18万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314407
• 关键词: Acute; Adrenal Cortex Hormones; Aerosols; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Asthma; Authorization documentation; Bioavailable; Biological Assay; Blood; Breathing; Bronchoalveolar Lavage; Canis familiaris; Cardiac; Caring; Cells; Characteristics; Child; Chronic; Clinical; Clinical Research; Clinical Trials; Data; Dermatophagoides Antigens; Disease; Doctor of Philosophy; Dose; Event; Excision; Experimental Designs; Foundations; Free Radicals; Generations; Goals; Goblet Cells; Human; IgE; Inbred BALB C Mice; Inflammation; Inflammation Mediators; Inflammatory; Inhalation Drug Administration; Injection of therapeutic agent; Interleukin-6; Intranasal Administration; Intravenous; Investigational Drugs; Investigational New Drug Application; Legal patent; Life; Lipopolysaccharides; Low Density Lipoprotein Receptor; Lung; Marketing; Measurement; Measures; Mediating; Medical; Messenger RNA; Methods; Modeling; Multiple Sclerosis; Mus; National Heart, Lung, and Blood Institute; Nebulizer; Nitric Oxide; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma; Positioning Attribute; Publications; Publishing; Puncture procedure; Pyroglyphidae; RNA; Rattus; Reporting; Resistance; Route; Safety; Series; Signs and Symptoms; Testing; Therapeutic; Tumor Necrosis Factor-alpha; United States; Whole Blood; Work; airway hyperresponsiveness; airway remodeling; asthmatic patient; base; cytokine; drug development; effective therapy; human disease; intravenous administration; meetings; methacholine; mimetics; mouse model; novel; novel strategies; pre-clinical; pulmonary function; research clinical testing; research study; response; safety study; success

DESCRIPTION (provided by applicant): Our overall goal is to market a COG compound (aka. apoE-mimetic peptides) for the treatment of patients with asthma. Cognosci has discovered, patented and published a novel series of COG compounds which are functional mimetics of apolipoprotein-E. These COG compounds have profound anti-inflammatory activities in a wide variety of cell-based and animal-based models of human disease conditions (Vitek et al. 2011, Christensen et al. 2011, Li et al. 2008, Lynch et al. 2003, and others). The COG compounds are also extremely well tolerated in mice, rats and dogs following repeated daily dosing for as many as 90 days that was tested. In a totally unanticipated publication, Levine and colleagues at National Institutes of Heart, Lung and Blood (NHLBI) independently found that apoE-130-149 significantly reduced the signs, symptoms and characteristics of asthma in a house dust mite-induced model of asthma in mice. ApoE-130-149 is known to us as COG130, a patented composition of matter owned by Cognosci. These events have now put us in a unique position to verify and extend Levine's pioneering work in this Phase I proposal so that we can: 1) show that COG130 can be efficiently nebulized into an aerosol, and that the inhaled aerosol is well tolerated in single and repeat dosing in mice and 2) that inhaled COG130 produces a dose-dependent reduction of asthmatic characteristics in a House Dust Mite-induced model of asthma in mice. The data generated from the successful completion of the experimental work plan in this proposal will lay the foundation for the medical, commercial and regulatory requirements that Cognosci will need to fully develop to move a COG compound into clinical use for the treatment of asthma. PUBLIC HEALTH RELEVANCE: Asthma is a highly prevalent disease affecting 300 million patients worldwide, with 24 million in the United States including 10 million children, and its numbers appear to be increasing. Sadly, in spite of our best efforts to provide medical care, 5000 asthmatic patients die each year from their disease (about 100 per week). Clearly we need new and more effective treatments to control asthma, particularly severe asthma that includes acute life-threatening situations. This proposal is to test a totally novel approach, where COG compounds, which are peptide mimetics of apolipoprotein-E, confer profound anti-inflammatory activity, reduce airway hyperresponsiveness and reduce airway remodeling that is associated with the asthmatic condition in mouse models. Based on the data collected in these proposed studies, we will be able to define how COG130 aerosols are tolerated in healthy mice and how they can reduce the signs and symptoms of disease in a house dust mite-induced model of asthma in mice. These studies are part of the foundation that we need to build to complete FDA required safety and toleratiblity studies in animals as a prelude to clinical testing in human asthmatic patients.

描述(由申请者提供)：我们的总体目标是销售COG化合物(又名。APOE模拟多肽)用于治疗哮喘患者。Cognosci发现、申请了专利并发表了一系列新的COG化合物，这些化合物是载脂蛋白-E的功能模拟物。这些COG化合物在多种基于细胞和动物的人类疾病模型中具有深刻的抗炎活性(Vitek等人。2011年，Christensen等人。2011年，Li et al.2008年，Lynch等人。2003年，以及其他)。COG化合物在小鼠、大鼠和狗身上的耐受性也非常好，经过长达90天的重复每日给药测试。在一篇完全出人意料的论文中，Levine和他在美国国立心肺血液研究所(NHLBI)的同事独立发现，apoE-130-149显著减少了室内尘螨诱导的小鼠哮喘模型中哮喘的体征、症状和特征。APOE-130-149被我们称为COG130，这是Cognosci拥有的一种专利物质组合物。这些事件现在使我们处于一个独特的地位，可以验证和扩展Levine在这一第一阶段提案中的开创性工作，以便我们能够：1)显示COG130可以有效地雾化成气雾剂，并且在小鼠单次和重复给药中耐受性良好，2)在屋尘螨诱导的小鼠哮喘模型中，吸入COG130可导致剂量依赖的哮喘特征减少。成功完成本提案中的实验工作计划所产生的数据将为Cognosci全面开发将COG化合物用于治疗哮喘的临床使用所需的医疗、商业和监管要求奠定基础。 公共卫生相关性：哮喘是一种高度流行的疾病，影响着全球3亿患者，美国有2400万患者，其中包括1000万儿童，而且其人数似乎还在增加。可悲的是，尽管我们尽了最大努力提供医疗护理，但每年仍有5000名哮喘患者死于他们的疾病(大约每周100人)。显然，我们需要新的更有效的治疗方法来控制哮喘，特别是包括危及生命的急性情况在内的严重哮喘。这项建议是为了测试一种全新的方法，在这种方法中，COG化合物是载脂蛋白-E的多肽模拟物，具有深刻的抗炎活性，降低小鼠的气道高反应性，并减少与哮喘相关的气道重塑。基于这些拟议研究中收集的数据，我们将能够确定健康小鼠对COG130气雾剂的耐受性，以及它们如何在屋尘螨诱导的小鼠哮喘模型中减少疾病的体征和症状。这些研究是我们需要建立的基础的一部分，以完成FDA要求的动物安全性和耐受性研究，作为对人类哮喘患者进行临床测试的前奏。