Development of SP-A Derived Peptidomimetics for the Treatment of Asthma - Phase II

用于治疗哮喘的 SP-A 衍生肽模拟物的开发 - II 期

• 批准号: 10708853
• 负责人: Scott Boitano
• 金额: $ 147.82万
• 依托单位: RAESEDO, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708853
• 关键词: Active Sites; Adaptive Immune System; Advanced Development; Aerosols; Ambrosia; Amino Acids; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Arizona; Asthma; Biological Assay; Biomedical Research; Canis familiaris; Cell physiology; Cells; Cessation of life; Characteristics; Collaborations; Complex; Custom; Data; Development; Disease; Documentation; Dose; Drug Kinetics; Drug Screening; Engineering; Environment; Epithelial Cells; Evaluation; Formulation; Goals; Good Manufacturing Process; Guidelines; Half-Life; Health Care Costs; Health Expenditures; Immune response; Immunomodulators; In Vitro; Induction of Apoptosis; Inflammatory; Inhalation; Inhalation Toxicology; Innate Immune System; Investigational New Drug Application; Lead; Lectin; Length; Liquid substance; Lung; Modeling; Modification; Morbidity - disease rate; Mucins; Patients; Peptide Hydrolases; Peptides; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Population; Prevalence; Process; Production; Productivity; Property; Proteins; Pulmonary Surfactant-Associated Protein A; Rattus; Reporting; Research Institute; Resolution; Respiratory Disease; Safety; Series; Structure; Symptoms; Systems Development; Testing; Therapeutic; Toxic effect; Toxicity Tests; Toxicology; Universities; Validation; Work; aerosolized; airway inflammation; analog; assay development; asthma exacerbation; asthma model; asthmatic; asthmatic patient; canine model; cellular targeting; constriction; design; eosinophil; improved; in vivo; inflammatory lung disease; inflammatory milieu; injured airway; innate immune function; lead candidate; manufacture; mimetics; mortality; mouse model; novel therapeutics; pathogen; patient subsets; peptidomimetics; pre-clinical; programs; pulmonary function decline; quality assurance; research clinical testing; response; side effect; small molecule

Current treatments for asthma, while reducing exacerbations in a subset of patients by focusing on airway inflammation, do not eliminate them. Asthma exacerbations are a significant cause of morbidity and mortality in asthma as they can lead to airway injury, lung function decline and death. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. There is no current innate immune modulator for the treatment of asthma. Thus, there is a critical need to develop new therapies to be used in the treatment of inflammatory lung diseases including asthma. We have discovered small molecules that mimic the effect of an endogenous lung protein, Surfactant Protein A (SP-A), in reducing airway constriction associated with asthma that causes symptoms and exacerbations. SP-A is a natural component of the lining fluid in the lungs and serves as a first line of defense against inhaled insults and pathogens. Many asthma patients have either very low levels of SP-A or damaged SP-A due to the inflammatory environment of the asthma lung. Full-length SP-A delivered directly to the lungs is not feasible due to its size and structure. Our company, RaeSedo Inc., was founded on the principle that we can create custom modifications of the active region of SP-A that are delivered in small peptidomimetic form that have improved pharmacokinetic properties and stability. These SP-A derived peptidomimetics represent a new class of asthma therapeutics. During Phase I, RaeSedo Inc. and the University of Arizona, worked to meet the milestones proposed: Design, synthesize and optimize peptidomimetics and to characterize the bioactivity of the peptidomimetics at specific cellular targets to identify lead compounds. RaeSedo Inc.’s objectives for the Phase II proposal are to advance aerosol development, pharmacology and evaluation of toxicity of our lead compounds (C867 and C892) in two large animal models through collaborations with the University of Arizona and Lovelace Biomedical. The overall goal of this phase II proposal is to demonstrate safety and efficacy in the ragweed sensitized canine model of asthma. If successful, RaeSedo Inc. will be equipped to submit an IND application bringing a new class of asthma therapeutics to the FDA for approval.

目前的哮喘治疗方法，同时通过关注气道来减少部分患者的病情加重 炎症，不要消除它们。哮喘恶化是发病的一个重要原因 哮喘死亡率，因为它们可导致气道损伤、肺功能下降和死亡。病情加重 更严重的哮喘患者尤其令人担忧，因为医疗费用和生产力损失导致 美国每年的医疗保健支出为 210 亿美元。目前尚无先天免疫调节剂 哮喘的治疗。因此，迫切需要开发新的疗法用于 治疗包括哮喘在内的炎症性肺部疾病。我们发现了小分子 模拟内源性肺蛋白表面活性蛋白 A (SP-A) 在缩小气道方面的作用 与哮喘相关的收缩，导致症状和恶化。 SP-A是一种天然的 肺部内壁液的组成部分，是抵御吸入性损伤的第一道防线 病原体。许多哮喘患者的 SP-A 水平要么非常低，要么由于哮喘导致 SP-A 受损。 哮喘肺部的炎症环境。直接输送到肺部的全长 SP-A 不是 由于其尺寸和结构而可行。 我们公司 RaeSedo Inc. 的成立原则是我们可以对产品进行定制修改 SP-A 的活性区域以小肽模拟物的形式传递，并得到了改善 药代动力学特性和稳定性。这些 SP-A 衍生的肽模拟物代表了一类新的 哮喘治疗。在第一阶段，RaeSedo Inc. 和亚利桑那大学致力于满足 提出的里程碑：设计、合成和优化肽模拟物并表征 肽模拟物对特定细胞靶标的生物活性，以鉴定先导化合物。 RaeSedo Inc. 的 第二阶段提案的目标是推进气雾剂的开发、药理学和评估 通过合作研究我们的先导化合物（C867 和 C892）在两个大型动物模型中的毒性 与亚利桑那大学和洛夫莱斯生物医学公司合作。第二阶段提案的总体目标是 在豚草致敏的犬哮喘模型中证明了安全性和有效性。如果成功的话， RaeSedo Inc. 将有能力提交 IND 申请，带来新类别的哮喘 治疗方案提交 FDA 批准。