Targeting the Immunometabolic Hub Nlrx1 as a Novel Therapeutic for Asthma

靶向免疫代谢中心 Nlrx1 作为哮喘的新型治疗方法

• 批准号: 10323994
• 负责人: Josep Bassaganya-Riera
• 金额: $ 36.15万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323994
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Airway Disease; Allergens; Allergic Disease; Alternaria; Ambrosia; American; Aspergillus; Asthma; Autoimmune Diseases; Benign; Binding; Biological; Biological Availability; Biological Response Modifier Therapy; Biotechnology; Blood; CD4 Positive T Lymphocytes; Cavia; Cells; Chronic; Chronic Disease; Clinical Trials; Communicable Diseases; Computer Models; Data; Dendritic Cells; Development; Disease; Dose; Drug Kinetics; Effectiveness; Epithelial Cells; Exposure to; Extrinsic asthma; Foundations; Goals; Growth; Half-Life; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL8 gene; IgE; Immune response; Immune signaling; Immunity; Immunoglobulin G; Individual; Industry; Inflammation; Inflammatory Response; Inhalation; Injections; Interleukin-6; Lead; Legal patent; Leucine-Rich Repeat; Lower Respiratory System; Lung; Mediating; Medical; Mitochondria; Mus; No-Observed-Adverse-Effect Level; Nucleotides; Oral; Outcome; Patients; Pharmaceutical Preparations; Phase; Physiological; Plasma; Pollen; Population; Precision Health; Program Development; Pyroglyphidae; Rattus; Recovery; Role; Safety; Small Business Innovation Research Grant; Specificity; Symptoms; T cell response; TSLP gene; Therapeutic; Time; Toxic effect; Toxicology; Translations; Treatment Efficacy; Validation; Visit; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; asthma model; asthmatic airway; asthmatic patient; commercial application; commercialization; cost; eosinophil; experimental study; immune function; in vivo; innovation; leucine-rich repeat protein; loss of function; mast cell; mouse model; neutrophil; new therapeutic target; novel; novel therapeutics; patient subsets; precision medicine; prevent; public health relevance; recruit; research and development; research clinical testing; respiratory; response; side effect; small molecule; small molecule therapeutics; stem; steroid dependence; success; therapeutic target

Targeting the Immunometabolic Hub Nlrx1 as a Novel Therapeutic for Allergic Asthma Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. This SBIR application stems from data showing a vital role for nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as a new therapeutic target for allergy and asthma. Our Product: BTI has developed first-in-class, small-molecule therapeutics that bind and activate the novel regulatory molecule, NLRX1. The goal of this project is to validate NLRX1 as a target for allergic asthma and develop NX-73 as an oral therapeutic to treat mild to moderate to severe asthma. Significance: Asthma is a chronic disease afflicting over 330 million individuals globally and 40 million in the U. S. Asthma is a chronic, widespread allergic disease with total expenses exceeding $80 billion annually in the U.S. In particular, neutrophilic, non-type 2 asthma has a lower responsiveness to current treatments. Though recent years have witnessed an increase in the number of biologics for asthma, these biologics are specific to certain endotypes, are very costly, and require up to 26 visits per year for treatment via injections. Inhaled corticosteroids, another common form of treatment have moderate to serious adverse side-effects and are thought to reduce in effectiveness overtime. Thus, there is an unmet medical need for safer and more efficacious oral therapeutics for asthma. This SBIR Phase I application will develop NX-73 as a novel NLRX1-binding product candidate and validate its safety, efficacy, and specificity for the NLRX1 target. Success in this project will launch a new drug development program centered on NLRX1-activating orally active therapeutics with a long-term goal of entering clinical trials for asthma by 2022. The Specific Aims are to: Aim 1. Determine the in vivo proof-of-concept therapeutic efficacy of NX-73 in mouse models of allergic asthma. Aim 2. Evaluate whether NX-73 reduces Th2 and/or Th17 responses by dendritic cells and airway epithelial cells. Aim 3. Conduct preliminary pharmacokinetic (PK) and toxicity studies with NX-73 to determine the oral bioavailability and pulmonary distribution and 7-day repeat-dose toxicity in rats. Expected Successful Outcomes: i) Validation of the therapeutic efficacy of NX-73 as a lead molecule for suppressing asthma by targeting Nlrx1; ii) Reduction of asthma symptoms with oral doses of NX-73 ≤ 10 mg/kg; iii) Loss of NX-73 function in Nlrx1-/- mice and cells; and iv) Benign safety profile with NOAEL ≥ 1,000 mg/kg oral in rats. SBIR Phase II: Will validate the translation of NX-73 effects in human CD141hi dendritic cells and airway epithelial cells from individuals with mild-to-moderate and moderate-to-severe asthma, assess the therapeutic efficacy of NX-73 in a guinea pig model of asthma, and advance NX-73 to IND-enabling GLP toxicology studies. Commercial Application: At the conclusion of this R&D effort BTI will have the preliminary validation necessary to select NX-73 as an IND-ready lead NLRX1-targeting small molecule. The impact of new oral, NLRX1-activating asthma therapeutics has the potential to disrupt a $56 billion industry that is anticipated to compound annual growth rate of 7%.

靶向免疫代谢枢纽Nlrx 1作为过敏性哮喘的新疗法 Biotherapeutics Inc（BTI）是一家新兴的生物技术公司，协同结合了先进的 计算建模与平移实验，以加速精密新产品的开发 医药和健康。SBIR的应用源于显示核苷酸结合寡聚化的重要作用的数据 结构域，富含亮氨酸重复序列的X1（NLRX 1）作为过敏和哮喘的新治疗靶点。 我们的产品：BTI开发了一流的小分子治疗剂，可以结合并激活新的调节因子， 分子，NLRX 1。该项目的目标是验证NLRX 1作为过敏性哮喘的靶点，并开发NX-73作为治疗过敏性哮喘的靶点 用于治疗轻度至中度至重度哮喘的口服治疗剂。 意义：哮喘是一种慢性疾病，全球有3.3亿人患有哮喘，美国有4000万人患有哮喘。S.哮喘 是一种慢性、广泛的过敏性疾病，在美国每年的总费用超过800亿美元。 嗜酸性粒细胞的非2型哮喘对当前治疗的反应性较低。尽管近年来， 随着用于哮喘的生物制剂数量的增加，这些生物制剂对某些内型是特异性的，非常昂贵， 每年最多26次注射治疗。吸入性皮质类固醇，另一种常见的治疗形式， 中度至严重的不良副作用，并被认为随着时间的推移有效性降低。因此，有一个未满足的医疗 需要更安全和更有效的哮喘口服治疗剂。该SBIR第一阶段应用将开发NX-73作为一种 新的NLRX 1结合产物候选物，并验证其对NLRX 1靶标的安全性、有效性和特异性。成功 该项目将启动一项以NLRX 1激活口服活性治疗药物为中心的新药开发计划， 到2022年进入哮喘临床试验的长期目标。具体目标是： 目标1.确定NX-73在过敏性哮喘小鼠模型中的体内概念验证治疗功效。 目标2.评估NX-73是否降低树突状细胞和气道上皮细胞的Th 2和/或Th 17应答。 目标3.使用NX-73进行初步药代动力学（PK）和毒性研究，以确定口服 生物利用度和肺部分布以及大鼠7天重复给药毒性。 i）确认NX-73作为抑制肿瘤生长的先导分子的治疗功效， 通过靶向Nlrx 1减轻哮喘; ii）口服剂量≤ 10 mg/kg的NX-73减轻哮喘症状; iii）NX-73损失 在Nlrx 1-/-小鼠和细胞中的功能;和iv）大鼠口服NOAEL ≥ 1，000 mg/kg的良性安全性特征。 SBIR II期：将验证NX-73在人CD 141 hi树突状细胞和气道上皮细胞中的作用 从轻度至中度和中度至重度哮喘个体中，评估NX-73在豚鼠中的治疗效果 猪哮喘模型，并推进NX-73 IND使GLP毒理学研究。 商业应用：在这项研发工作结束时，BTI将进行选择所需的初步验证 NX-73作为IND准备的NLRX 1靶向小分子。新的口服NLRX 1激活哮喘的影响 治疗有可能破坏一个560亿美元的行业，预计复合年增长率为7%。