An Inhaled Microbiome-Targeted Biotherapeutic for Treatment of COPD

一种吸入性微生物组靶向生物治疗药物，用于治疗慢性阻塞性肺病

• 批准号: 10600887
• 负责人: Teodora NICOLA
• 金额: $ 29.53万
• 依托单位: RESBIOTIC, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600887
• 关键词: Acetylation; Acute; Address; Adrenal Cortex Hormones; Affect; American; Animals; Anti-Inflammatory Agents; Bacteria; Biological Response Modifier Therapy; Biology; Bronchodilator Agents; Cause of Death; Cell Culture Techniques; Cell model; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Collaborations; Combined Modality Therapy; Complementary therapies; Data; Degenerative Disorder; Development; Disease; Disease Progression; Disease model; Dose; Drug Formulations; Dryness; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Degradation; Formulation; Frequencies; Future; Gelatinase B; Generations; Glycine; Goals; Health Status; Human; In Vitro; Inflammation; Inflammatory; Inhalation; Inhalation Device; Interleukin-1 beta; Interleukin-8; Lactic acid; Lactobacillus; Lactobacillus acidophilus; Lactobacillus casei rhamnosus; Lactobacillus plantarum; Lead; Legal patent; Leukocyte Elastase; Licensing; Lipopolysaccharides; Lung; Lung diseases; Mammals; Modality; Modeling; Monitor; Mus; Particle Size; Patients; Peptide Hydrolases; Peptides; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Phosphodiesterase Inhibitors; Pneumonia; Powder dose form; Probiotics; Process; Production; Proline; Property; Proteobacteria; Pulmonary Inflammation; Quality of life; Research; Respiratory Disease; Respiratory Stimulants; Safety; Smoking; Symptoms; TNF gene; Teichoic Acids; Testing; Therapeutic; Toxicology; Woman; airway remodeling; alternative treatment; bronchial epithelium; chemical stability; chemokine; chronic inflammatory lung disease; clinical efficacy; commercialization; comparison control; cytokine; density; dosage; drug development; drug inhalation; dysbiosis; efficacy evaluation; efficacy study; efficacy testing; exosome; experience; exposed human population; first-in-human; improved; in vivo; lead candidate; lung microbiome; men; microbial; microbiome; microbiome alteration; microbiome research; mortality risk; mouse model; neutrophil; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; pulmonary function; recruit; safety assessment; safety testing; screening; side effect; standard of care; therapeutic candidate; tobacco smoke exposure; treatment response

PROJECT SUMMARY - ResBiotic Inc. is developing its lead drug product, RB1000, a spray-dried powder com- prised of an inhaled biotherapeutic API for treatment of neutrophilic inflammation and disease progression in COPD patients. COPD is a chronic degenerative disease that is the fourth leading cause of death in the U.S., where it predominantly results from tobacco smoke exposure. Acute exacerbations are a sudden worsening of symptoms that can occur frequently, ≥ 2 per year in severe cases, and can result in reduced lung function, reduced health status, and increased risk for mortality. Treatment approaches including short- and long-acting bronchodilators, corticosteroids, phosphodiesterase inhibitors, cytokine blockers, and respiratory stimulants have been used but with limited clinical efficacy. Inhaled corticosteroids are used specifically to treat inflamma- tion but have potential for serious side effects, e.g., severe pneumonia and death. Combination therapies have demonstrated modest reductions in exacerbation frequency, but there is still significant room for improvement, as these therapeutics do not halt disease progression and often can have serious side effects. Recent research has demonstrated a strong association between neutrophilic inflammation that results from dysbiosis, i.e., an altered microbiome, of the lung in COPD. ResBiotic has demonstrated that heightened levels of proteobacteria can increase expression of matrix metalloproteinase 9 (MMP-9) and neutrophil elastase (NE), which are associ- ated with neutrophilic inflammation and can cause extracellular matrix degradation and airway remodeling. Res- Biotic has demonstrated in vitro and in vivo that anti-inflammatory Lactobacillus strains can reduce inflammation resulting from dysbiosis, including the expression of MMP-9 and NE, which may enable highly effective biother- apeutic drugs for COPD. Commercialization of a Lactobacillus-based biotherapeutic drug would provide an al- ternative anti-inflammatory approach with a different mechanism of action than currently available therapeutics. The goal of this proposal will be to develop a biotherapeutic drug that includes non-living components of a Lac- tobacillus bacterial extract that are responsible for the therapeutic response. Phase I will include screening dif- ferent cellular components at various dosages to identify several candidates that reduce MMP-9 expression in primary human bronchial epithelial cells taken from COPD patients. Phase II will include the development of a dry powder formulation of optimal candidates and safety and efficacy testing in preclinical mouse models of COPD. The deliverable for Phase II will be a lead candidate that has demonstrated efficacy in reduction of neutrophilic inflammation and improvements in lung function that is ready to advance to IND-enabling large mammal studies. Successful commercialization of the inhaled drug product RB1000 is expected to provide an alternative or complementary treatment modality to the standard of care to address neutrophilic inflammation resulting from dysbiosis in COPD, which is expected to reduce COPD exacerbations, potentially reduce disease progression, and improve patient quality of life.

项目概要- ResBiotic Inc.正在开发其主要药物产品RB 1000，一种喷雾干燥的粉末组合物， 一种吸入性双氯芬酸API，用于治疗 COPD患者。COPD是一种慢性退行性疾病，是美国第四大死亡原因， 主要是由于接触烟草烟雾。急性加重是指 症状可能频繁发生，严重病例中每年≥ 2次，并可能导致肺功能降低， 健康状况下降，死亡风险增加。治疗方法，包括短效和长效 支气管扩张剂、皮质类固醇、磷酸二酯酶抑制剂、细胞因子阻滞剂和呼吸兴奋剂 但临床疗效有限。吸入性皮质类固醇专门用于治疗炎症- 但有可能产生严重的副作用，例如，严重的肺炎和死亡。联合疗法具有 显示出加重频率的适度降低，但仍有显著的改善空间， 因为这些治疗剂不能阻止疾病的进展，并且常常具有严重的副作用。最近的研究 已经证明了由生态失调引起的嗜酸性炎症，即，一个 改变了COPD患者肺部的微生物组。ResBiotic已经证明， 可增加基质金属蛋白酶9（MMP-9）和中性粒细胞弹性蛋白酶（NE）的表达，这两种蛋白酶与肿瘤的发生有关。 与嗜酸性炎症相关，并可导致细胞外基质降解和气道重塑。Res- Biotic已经在体外和体内证明了抗炎乳酸菌菌株可以减少炎症 由生态失调引起的，包括MMP-9和NE的表达，这可能使高效的生物治疗成为可能。 治疗COPD的药物。基于乳酸杆菌的生物素药物的商业化将提供一种新的方法， 具有与目前可用的治疗剂不同的作用机制的替代抗炎方法。 该提案的目标是开发一种生物活性药物，其中包括Lac的非生命成分， 负责治疗反应的抗菌提取物。第一阶段将包括筛选差异- 不同剂量的细胞组分，以鉴定几种降低MMP-9表达的候选物。 取自COPD患者的原代人支气管上皮细胞。第二阶段将包括开发一个 最佳候选物的干粉制剂以及在临床前小鼠模型中的安全性和功效测试 慢性阻塞性肺病第二阶段的可交付成果将是一种主要候选产品，已证明其在减少 嗜酸性炎症和肺功能的改善，准备推进到IND使能性大 哺乳动物研究吸入药物产品RB 1000的成功商业化预计将提供一个 标准治疗的替代或补充治疗方式，以解决嗜酸性炎症 预期可减少COPD急性加重，潜在地减少疾病 改善患者的生活质量。