A Novel Synthetic Biology-Derived Microbiome Therapeutic to Treat Viral-Induced Acute Respiratory Distress Syndrome (ARDS)

一种新型合成生物学衍生的微生物疗法，可治疗病毒引起的急性呼吸窘迫综合征（ARDS）

• 批准号: 10601865
• 负责人: Gary Fanger
• 金额: $ 102.66万
• 依托单位: RISE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-17 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601865
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Affect; Animal Model; Antigens; Biological Markers; Biology; Cell Line; Cells; Chemistry; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Complication; Coronavirus Infections; Data; Defense Mechanisms; Dendritic Cells; Development; Diet; Disease; Dose; Down-Regulation; Drug Kinetics; Drug toxicity; Economics; Educational process of instructing; Effector Cell; Engineering; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Equilibrium; Evaluation; Flow Cytometry; Food Industry; Funding; Future; General Population; Genes; Grant; Health; Hematology; Histopathology; Human; Hyperactivity; Immune; Immune response; Immune system; Immunity; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Influenza; Infrastructure; Ingestion; Innate Immune Response; Intestines; Investments; Lactococcus lactis; Leukocytes; Life; Link; Lung; Measures; Mediating; Medicine; Modeling; Mucous Membrane; Mus; Neutrophil Activation; Neutrophil Infiltration; Neutrophilia; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Population; Positioning Attribute; Probiotics; Process; Proteins; Regulatory T-Lymphocyte; Role; Safety; Severities; Severity of illness; Small Business Innovation Research Grant; Surface; T-Lymphocyte; Temperature; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Toxicology; Up-Regulation; Viral; Virus Diseases; White Blood Cell Count procedure; Work; airway epithelium; biomarker identification; capsule; current pandemic; cytokine; drug development; gut microbiome; gut microbiota; immunoregulation; influenza infection; innovation; lung injury; lung microbiome; manufacture; microbial; microbiome; microbiome therapeutics; mouse model; mutational status; neutrophil; novel; novel marker; novel strategies; novel therapeutics; pandemic disease; pathogen; pathogenic virus; programs; research clinical testing; respiratory virus; screening; synthetic biology; targeted delivery

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a severe life-threatening complication that can be caused by viral infection. The disease is characterized by cytokine-driven hyperinflammation and leukocytes count changes. The innate immune response has been linked to ARDS immunopathogenesis. In this regard, neutrophils have been highlighted as essential effector cells in the development of ARDS, as demonstrated in influenza and coronavirus infections. Therefore, therapeutic strategies targeting hyperactivated neutrophils may be useful for mitigating ARDS. The gut microbiota has emerged as an important regulator of the host immunity. Microbial components from the gut microbiota can regulate neutrophil functions, modulating the magnitude of inflammatory responses not only locally, but also systemically. The gut-lung microbiome connection implicates the gut microbiome as a relevant new strategy to lessen disease severity in viral-mediated ARDS. The current pandemic has taught us that we need novel, revolutionary therapies that can be deployed quickly and easily to the general population worldwide. In the context of viral-induced ARDS, targeting neutrophils, restoring airways epithelial cell barrier, and refocusing the immune response represents a critical and novel strategy that is neither limited by our understanding of the viral pathogens` biology nor by antigenicity or mutational status but can act broadly by leveraging the existing host immune repertoire. Rise Therapeutics is developing R-3750, a functionally directed synthetic probiotic that engages natural microbiome-associated immunological processes with the potential to diminish lung neutrophilia, reduce inflammation, upregulate regulatory T cells, and restore airways epithelial barrier to balance and reset patient’s immunological repertoire. R-3750 is inexpensive to manufacture, is orally dosed, and is stored stably at room temperature. R-3750, Lactococcus (L.) lactis engineered to express Surface Layer Protein A (SlpA), works via oral targeted delivery of SlpA to the intestinal tract where it engages mucosal dendritic cells lining the intestinal tract to reset immunological repertoires to blunt inflammatory processes. R-3750 induces exquisite differential gene expression leading to upregulation of anti-viral defense mechanisms and down-regulation of pro- inflammatory pathways. No safety issues for R-3750 have ever been noticed in animal models, and L. lactis is commonly ingested in our diet, as this strain is used as a probiotic and in the food industry. This Phase II proposal seeks funding to identify novel biomarkers and further understand R-3750 mechanism of action in several models of lung injuries, while completing key IND-enabling activities. R-3750 represents a new revolutionary therapy that combines the safety, economics, and ease of administration of a probiotic with the targeted delivery of an immunologically relevant protein that can quickly be deployed to save lives of virally infected patients with a hyperactive immune response.

项目概要 急性呼吸窘迫综合征 (ARDS) 是一种严重危及生命的并发症，可由以下原因引起： 该疾病的特征是细胞因子驱动的过度炎症和白细胞计数。 在这方面，先天免疫反应与 ARDS 免疫发病机制有关。 中性粒细胞已被强调为 ARDS 发展中的重要效应细胞，如 因此，针对过度活跃的中性粒细胞的治疗策略。 可能有助于缓解 ARDS。 肠道微生物群已成为宿主免疫微生物成分的重要调节剂。 肠道微生物群可以调节中性粒细胞功能，调节炎症反应的程度 肠道-肺微生物组的联系不仅限于局部，而且还涉及全身。 减轻病毒介导的 ARDS 疾病严重程度的相关新策略。 当前的大流行告诉我们，我们需要可以快速部署的新颖、革命性疗法 在病毒引起的 ARDS 的背景下，针对中性粒细胞， 恢复气道上皮细胞屏障并重新集中免疫反应代表了一种关键且新颖的方法 策略既不受我们对病毒病原体生物学的理解的限制，也不受抗原性或 突变状态，但可以通过利用现有的宿主免疫库广泛发挥作用。 Rise Therapeutics 正在开发 R-3750，这是一种功能导向的合成益生菌，可结合天然 微生物组相关的免疫过程有可能减少肺中性粒细胞增多，减少 炎症，上调调节性 T 细胞，恢复气道上皮屏障，以平衡和重置患者的 R-3750 制造成本低廉，口服给药，并可在室内稳定保存。 R-3750，乳酸乳球菌 (L.)，经过改造可表达表面层蛋白 A (SlpA)，通过以下方式发挥作用： SlpA 口服靶向递送至肠道，与肠道内的粘膜树突状细胞结合 R-3750 可以重置免疫系统，从而减弱炎症过程。 基因表达导致抗病毒防御机制上调和亲病毒防御机制下调 在动物模型中尚未发现 R-3750 的安全性问题，而乳酸乳球菌是这样的。 通常在我们的饮食中摄入，因为该菌株被用作益生菌并用于食品工业。 该第二阶段提案寻求资金来识别新型生物标志物并进一步了解 R-3750 机制 R-3750 在多种肺损伤模型中发挥作用，同时完成关键的 IND 支持活动。 新的革命性疗法将益生菌的安全性、经济性和易于管理与 靶向递送免疫相关蛋白，可快速部署以挽救病​​毒感染者的生命 免疫反应过度活跃的感染患者。