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.

当前对哮喘的治疗方法，同时通过关注气道减少患者子集的加重 炎症，不要消除它们。哮喘恶化是发病率和 哮喘的死亡率可能导致气道损伤，肺功能下降和死亡。加重 更严重的哮喘患者特别关心 美国年度医疗保健支出为210亿美元。目前没有先天性免疫调节剂 哮喘的治疗。那是迫切需要开发新疗法以在 包括哮喘在内的炎症性肺部疾病的治疗。我们发现了小分子 模仿内源性肺蛋白表面活性剂蛋白A（SP-A）的作用在还原气道中 与哮喘有关的收缩会导致症状和恶化。 SP-A是自然的 肺中衬里液的成分，是针对遗传伤害的第一道防线 病原体。许多哮喘患者的SP-A水平非常低，或者由于SP-A损坏 哮喘肺的炎症环境。直接传递到肺部的全长SP-A不是 由于其大小和结构而可行。 我们的公司Raesedo Inc.的成立是根据我们可以创建自定义修改的原则 SP-A的活性区域以小胡椒形式进行了改善 药代动力学特性和稳定性。这些SP-A衍生的肽仪代表了一个新类 哮喘治疗。在第一阶段，Raesedo Inc.和亚利桑那大学，努力与 提出的里程碑：设计，合成和优化辣妹并表征 在特定细胞靶标上辣妹的生物活性以鉴定铅化合物。 Raesedo Inc.的 第二阶段提案的目标是提高气溶胶开发，药理学和评估 通过合作，我们的铅化合物的毒性（C867和C892）具有 与亚利桑那大学和Lovelace生物医学。该第二阶段提案的总体目标是 证明哮喘的Ragweed敏感犬模型的安全性和效率。如果成功， Raesedo Inc.将有能力提交IND申请，带来新的哮喘类 对FDA的治疗以供批准。