Targeting lipid rafts for treatment of asthma

靶向脂筏治疗哮喘

• 批准号: 10697410
• 负责人: DAVID H BROIDE
• 金额: $ 100万
• 依托单位: RAFT PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697410
• 关键词: Acute; Acute Lung Injury; Adaptive Immune System; Adrenal Cortex Hormones; Affect; Agonist; Amino Acid Sequence; Anti-Inflammatory Agents; Apolipoprotein A-I; Asthma; Autopsy; B-Lymphocytes; Binding Proteins; Biological; Biological Assay; Biological Products; Blood Vessels; Bronchoconstriction; Bronchodilator Agents; C-terminal; Cell membrane; Cell physiology; Cells; Cholesterol; Clinical Trials; Complex; Cyclic GMP; Development; Disease; Dose; Eosinophilia; Epithelial Cells; Epithelium; Excision; Formulation; Grant; Health; Human; Immune; Infection; Inflammation; Inflammatory; Inhalation; Innate Immune System; Interleukin-13; Interleukin-4; Ion Channel; Laboratories; Life; Ligand Binding; Lung; Macrophage; Membrane Microdomains; Methods; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; Neutrophilia; Organ; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Preventive therapy; Preventive treatment; Process; Proteins; Protocols documentation; Pulmonary Inflammation; Pyroglyphidae; Quality of life; Rattus; Reporting; Rhinovirus; Rhinovirus infection; Safety; Signal Transduction; Slice; Steroid Resistance; Structure of parenchyma of lung; T-Lymphocyte; TLR4 gene; Testing; Therapeutic Agents; Toxicology; Transcriptional Regulation; Variant; Viral; Virus Diseases; airway hyperresponsiveness; asthma exacerbation; asthma model; asthmatic; bronchial epithelium; cytokine; dimer; drug development; efficacy evaluation; efficacy study; efficacy testing; experimental study; improved; manufacture; mast cell; meetings; mouse model; neuroinflammation; neutrophil; novel; novel therapeutic intervention; novel therapeutics; patient subsets; persistent symptom; phase 2 study; pre-Investigational New Drug meeting; pre-clinical assessment; pulmonary function; receptor; response; safety assessment; safety study; standard of care; targeted treatment; therapy development; transcriptome sequencing

PROJECT SUMMARY Patients with severe asthma who display persistent bronchoconstriction and/or reduced lung function despite available bronchodilator, corticosteroid and Th2-targeting therapy develop significant morbidity, which severely impacts their quality of life owing to persistent symptoms, as well as frequent and life-threatening exacerbations. Aspects of severe asthma currently not managed by available therapies may display a strong inflammatory component driven by the innate and adaptive immune systems, particularly following viral exacerbations. Development of new therapeutic strategies targeting a wide range of inflammatory mechanisms, not only Th2 and Th1/Th17 responses, is needed to control severe asthma. Raft Pharmaceuticals proposes a new target for treatment of severe asthma – overabundant and clustered, pathological lipid rafts in bronchial epithelial and immune cells in asthmatics. Cholesterol-rich lipid rafts provide ordered plasma membrane domains, where receptors, ion channels and adaptor molecules can associate to form functional complexes. Large lipid rafts are required as the landing pad for microbes on host cells and for initiation of many inflammatory processes in bronchial epithelial and immune cells. We discovered apoA-I binding protein (AIBP) as a molecule that selectively targets the cholesterol depletion machinery to pathologic lipid rafts in inflammatory cells, without affecting homeostatic cellular function. The latter explains an exceptional safety profile of AIBP in mice and rats. In the Phase I of this grant, using mouse models of asthma, we demonstrated that administration of a biologic derived from the AIBP protein, was effective in an acute HDM model of asthma in mice, reducing airway hyperresponsiveness, airway eosinophilia, and expression of Th2 cytokines and epithelial alarmins. In a model of severe asthma, AIBP significantly reduced pulmonary neutrophilia. For Phase II proposal, a team of experts in biologic drug development and in preclinical assessment and clinical trials of therapeutic agents in asthma has been assembled to further the characterization of an improved AIBP sequence, RFT1124, as a development candidate for severe asthma. Specifically, we plan to manufacture and release RFT1124 drug product for efficacy and toxicology studies using cGMP-compatible processes and analytical assays. The efficacy of RFT1124 as an add-on therapy to standard-of-care inhaled corticosteroids and long-acting beta-agonists (ICS+LABA) will be tested in mouse models of asthma exacerbated by rhinovirus (RV) infection. In addition, we will use precision cut lung slices from asthmatics and non-asthmatics postmortem lung tissue to test the efficacy of add-on RFT1124 in ICS+LABA treatment in RV infected human airways. RNAseq studies will establish whether RFT1124 inhibits corticosteroid insensitive anti-inflammatory pathways and/or enhances corticosteroid sensitive pathways in RV infected human bronchial epithelial cells. Further, a non-GLP safety assessment of intranasal delivery of RFT1124 will be conducted to establish an estimate of safety margin and target organs. These results will be used to prepare for and conduct pre-IND (Type B) meeting with the FDA.

项目概要 尽管患有严重哮喘，但仍表现出持续支气管收缩和/或肺功能下降的患者 现有的支气管扩张剂、皮质类固醇和 Th2 靶向治疗会导致严重的发病率 由于持续的症状以及频繁且危及生命的病情恶化，影响了他们的生活质量。 目前可用疗法无法治疗的严重哮喘可能表现出强烈的炎症 由先天性和适应性免疫系统驱动的成分，特别是在病毒恶化后。 开发针对多种炎症机制（而不仅仅是 Th2）的新治疗策略 Raft Pharmaceuticals 提出了控制严重哮喘的新目标。 严重哮喘的治疗——支气管上皮和支气管上皮细胞中过多且聚集的病理性脂筏 哮喘患者体内富含胆固醇的免疫细胞提供有序的质膜结构域，其中 受体、离子通道和接头分子可以结合形成大的脂筏。 作为微生物在宿主细胞上的着陆垫以及启动许多炎症过程所需的 我们发现 apoA-I 结合蛋白 (AIBP) 作为一种选择性分子。 将胆固醇消耗机制靶向炎症细胞中的病理性脂筏，而不影响 后者解释了 AIBP 在小鼠和大鼠中的特殊安全性。 这项资助的第一阶段，使用哮喘小鼠模型，我们证明了施用生物衍生的药物 来自 AIBP 蛋白，对小鼠哮喘急性 HDM 模型有效，可减少气道 模型中的高反应性、气道嗜酸性粒细胞增多以及 Th2 细胞因子和上皮警报素的表达。 对于严重哮喘，AIBP 显着降低了肺中性粒细胞增多，针对 II 期建议，专家小组提出了这一建议。 生物药物开发以及哮喘治疗药物的临床前评估和临床试验 已组装以进一步表征改进的 AIBP 序列 RFT1124，作为一项开发 具体来说，我们计划生产和发布 RFT1124 药品以提高疗效。 使用 cGMP 兼容流程和分析测定进行毒理学研究 RFT1124 的功效。 标准护理吸入皮质类固醇和长效 β 受体激动剂 (ICS+LABA) 的附加疗法将是 在因鼻病毒（RV）感染而加剧的哮喘小鼠模型中进行了测试此外，我们将使用精确度。 从哮喘患者和非哮喘患者死后肺组织中切下肺切片，以测试附加的功效 RFT1124 在 RV 感染的人类呼吸道中的 ICS+LABA 治疗中是否会确定。 RFT1124 抑制皮质类固醇不敏感的抗炎途径和/或增强皮质类固醇敏感性 RV 感染的人支气管上皮细胞中的途径此外，鼻内的非 GLP 安全性评估。 RFT1124的交付将用于建立安全裕度和目标器官的估计这些结果。 将用于准备并与 FDA 举行 IND 前（B 类）会议。