Validation of Immunometabolic NLRX1 Therapeutics for IBD

IBD 免疫代谢 NLRX1 疗法的验证

基本信息

批准号：
10163181
负责人：
Andrew Leber
金额：
$ 64.34万
依托单位：
BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163181
关键词：
Aerobic Agonist Anti-Inflammatory Agents Autoimmune Diseases Bacteroidetes Benign Binding Biological Assay Biological Availability Biological Markers Biological Response Modifier Therapy Biotechnology Blood CD4 Positive T Lymphocytes Calorimetry Canis familiaris Cells Cessation of life Chronic Clinical Clinical Trials Colitis Colorectal Cancer Computer Models Data Deposition Development Disease Disease Management Dose Drug Kinetics Ecology Epithelial Cells Evaluation Extracellular Matrix Family Fibroblasts Fibrosis Firmicutes Gastrointestinal tract structure Gene Expression Glutamine Goals Human Hydrogen Peroxide Immune response Immunophenotyping In Situ In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferon Type II Knock-out Knowledge Lead Legal patent Lesion Leucine-Rich Repeat Ligands Long-Term Effects Lung diseases Malignant Neoplasms Measures Mediating Medical Metabolism Methods Mitochondria Modeling Mucous Membrane Mus Myeloid Cells No-Observed-Adverse-Effect Level Nucleotides Operative Surgical Procedures Oral Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phenotype Positioning Attribute Precision Health Production Program Development Proteins Rattus Recombinants Role Safety Severity of illness Signal Pathway Small Business Innovation Research Grant Specificity Spectrum Analysis T-Lymphocyte TNF gene Testing Therapeutic Toxic effect Treatment Efficacy Trichrome stain method United States Up-Regulation Validation Viral commensal bacteria commercial application cytokine drug development gut microbiome gut microbiota healing immune checkpoint inflammatory disease of the intestine innovation metabolic phenotype microbial microbiome sequencing microbiome signature mitochondrial metabolism mouse model new therapeutic target novel novel therapeutics precision medicine preference prophylactic public health relevance receptor research and development research clinical testing response safety study side effect small molecule small molecule therapeutics stem success

项目摘要

Validation of Immunometabolic NLRX1 Therapeutics for IBD 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 IBD. Our Product: BTI has identified the first family of small-molecule compounds that bind and activate the novel regulatory molecule, NLRX1. In a Phase I SBIR, we successfully established NX-13 as a NLRX1-specific agonist that reduces inflammatory lesions by 90% in CD4+ T cell-specific immunometabolic mechanisms. Background: IBD is a chronic widespread and debilitating illness that afflicts over 5 million people worldwide with total expenses exceeding $15 billion annually in the U.S alone. Current treatments are only modestly successful with significant adverse side effects. Thus, there is an unmet clinical need for safer, more efficacious IBD therapeutics. NLRX1 can suppress intestinal inflammation during infections and autoimmune disorders. BTI has validated that loss of NLRX1 causes reduced mucosal healing, increased fibrosis, >5-fold up-regulation in inflammatory cytokine biomarkers, and complete restructuring of gut microbiome ecology during IBD. This SBIR Phase II application will characterize microbial and anti-fibrotic mechanisms of NX-13, demonstrate translational efficacy in human UC primary cells and conduct IND-enabling safety studies. The Specific Aims are to: AIM 1. Determine the effect of NX-13 on the intestinal microbiome during colitis through 16S gut microbiome sequencing and signatures of gut-microbiome interactions. AIM 2. Characterize the anti-fibrotic mechanisms of NX-13 in chronic colitis models and in vitro effects on fibroblast gene expression and extracellular matrix deposition. AIM 3. Validate the translational efficacy of NX-13 in PBMCs and LPMCs from UC patients through evaluation of overall cellular response and CD4-specific immunometabolic mechanisms. AIM 4. Conduct an IND-enabling GLP toxicity study in a non-rodent species with a 28-day repeat dose toxicity study at three dose levels (250, 500, 1000 mg/kg) compared to vehicle. Expected Outcomes: Validation of NX-13 as a lead agonistic molecule for targeting NLRX1 through: i) identification of gut microbial and anti-fibrotic mechanisms of NX-13; ii) 50% reduction in TNFα and IFNγ production in human PBMCs and LPMCs; and iii) a benign safety profile with oral NOAEL ≥ 1,000 mg/kg. Commercial Application: Success in this project will launch a new drug development pipeline centered on NLRX1-activating therapeutics with anti-inflammatory and anti-fibrotic effects. BTI’s new NLRX1-targeting oral therapeutics could disrupt a market of over $10B annually growing at 25% annual rates.

IBD的免疫代谢NLRX1治疗剂的验证 Biotherapeutics Inc（BTI）是一家新兴的生物技术公司，协同结合了高级的力量通过转化实验进行计算建模，以加速新产品的开发精密医学和健康。该SBIR应用程序从数据中得出的步骤，显示核苷酸结合的重要作用寡聚结构域，含有X1（NLRX1）作为IBD的新治疗靶标的浅亮氨酸重复。我们的产品：BTI已经确定了绑定和激活新颖的小分子化合物的第一个家族调节分子，NLRX1。在I期SBIR中，我们成功地将NX-13建立为NLRX1特异性激动剂这将CD4+ T细胞特异性免疫代谢机制中的炎症病变降低了90％。背景：IBD是一种慢性宽度和使人衰弱的疾病，在全球范围内遭受超过500万人的困扰仅在美国，每年的总费用超过150亿美元。当前的治疗只是适度成功，具有明显的不良副作用。那就是对更安全，更高效的临床需求未满足 IBD疗法。 NLRX1可以在感染和自身免疫性疾病期间抑制肠道注射。 BTI 已经验证了NLRX1的丧失会导致粘膜愈合降低，纤维化增加，> 5倍上调 IBD期间，炎性细胞因子生物标志物以及肠道微生物组生态的完整恢复。这个Sbir II期应用将表征NX-13的微生物和抗纤维化机制，证明人类UC原代细胞的翻译效率并进行辅助安全研究。具体目的是： AIM 1。确定NX-13对结肠炎期间16S肠内肠道微生物组的影响肠道微生物组相互作用的微生物组测序和特征。 AIM 2。表征NX-13在慢性结肠炎模型中的抗纤维化机制，并对体外影响成纤维细胞基因表达和细胞外基质沉积。 AIM 3。通过UC患者从PBMC和LPMC中验证NX-13的转化效率评估整体细胞反应和CD4特异性免疫代谢机制。 AIM 4。在具有28天重复剂量的非腐蚀物种中进行辅助GLP毒性研究与媒介物相比，毒性研究的三个剂量水平（250、500、1000 mg/kg）。预期结果：验证NX-13作为靶向NLRX1的铅激动分子：i） NX-13的肠道微生物和抗纤维化机制的鉴定； ii）TNFα和IFNγ降低50％人类PBMC和LPMC的生产； iii）良性安全性，口服noael≥1,000mg/kg。商业应用：该项目的成功将启动以焦点为中心的新药开发管道 NLRX1激活疗法具有抗炎和抗纤维化作用。 BTI的新NLRX1靶向口服治疗可能会以每年25％的年率增长10B美元以上的市场。