Immunometabolic NLRX1 Therapeutics for IBD

IBD 免疫代谢 NLRX1 疗法

• 批准号: 9769332
• 负责人: Andrew Leber
• 金额: $ 23.32万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769332
• 关键词: ADME Study; Aerobic; Anti-inflammatory; Autoimmune Diseases; Benign; Binding; Binding Proteins; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biotechnology; Calorimetry; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Colitis; Colorectal Cancer; Computer Simulation; Data; Development; Disease; Disease Management; Disease Pathway; Dose; Ecology; Epithelial; Epithelial Cells; Family; Fibrosis; Gastrointestinal tract structure; Gene Expression; Goals; Human; Immune; Immune response; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Fibrosis; Knock-out; Knockout Mice; Knowledge; Lead; Legal patent; Leucine-Rich Repeat; Ligands; Long-Term Effects; Lung diseases; Malignant Neoplasms; Mediating; Medical; Methods; Mitochondria; Modeling; Mucous Membrane; Mus; Myelogenous; Myeloid Cells; No-Observed-Adverse-Effect Level; Nucleotides; Oral; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Plasma Proteins; Positioning Attribute; Precision Health; Program Development; Proteins; Rattus; Recombinants; Role; Safety; Severity of illness; Site; Small Business Innovation Research Grant; Specificity; Spectrum Analysis; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; United States; Up-Regulation; Validation; Viral; Work; base; commensal bacteria; commercial application; cytokine; drug development; gut microbiome; gut microbiota; healing; immune checkpoint; in vivo; innovation; mouse model; mutant; new therapeutic target; novel; novel therapeutics; off-patent; precision medicine; preference; public health relevance; receptor; research and development; safety study; side effect; single cell sequencing; small molecule; small molecule therapeutics; stem; success

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. The goal of this project is to validate NLRX1 as a target and develop NX-13 as the lead NLRX1-based, oral first-in-class therapeutic for IBD. Background: IBD is a chronic widespread and debilitating illness that afflicts over 5 million people worldwide. Current treatments are only modestly successful with significant adverse side effects, including cancer, infection and death. 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. Additionally, our top NLRX1 ligand exerts therapeutic actions in models of IBD. This SBIR Phase I application will characterize ligand- protein interactions of NX-13 and NLRX1, define the NX-13 cellular mechanism of action and validate its safety and specificity to NLRX1. The Specific Aims are to: AIM 1. Evaluate NX-13 interactions with purified and in situ NLRX1 by CD-spectroscopy and isothermal calorimetry on purified WT and mutant NLRX1 and by cellular thermal shift assays. AIM 2. Determine the cellular mechanism of action of NX-13 in vivo in the DSS model of colitis using cre- lox cell specific (CD4+, myeloid, epithelial) knockouts of NLRX1. AIM 3. Conduct preliminary ADME-Tox and specificity assays with NX-13 in off-target binding assays, 7- d dose-range finding toxicity studies in rats and ADME-Tox assays (hERG, Ames, CYP450, P-gp). Expected Outcomes: Validation of NX-13 as a lead molecule for targeting NLRX1 through: i) engagement of NLRX1 in situ at concentrations ≤ 0.1 µM); ii) identification of cellular mechanism of action by loss of efficacy in cell specific KO mice; iii) a benign safety profile with NOAEL ≥ 1,000 mg/kg oral in rats. SBIR Phase II will validate the implication of NLRX1 in human IBD, determine PK in rats, define anti-fibrotic effects in mouse models of intestinal fibrosis and advance NX-13 to IND-enabling GLP toxicology studies. Commercial Application: Success in this project will launch a new drug development pipeline at BTI 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NLRX 1治疗剂 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，以加速新产品的开发， 精准医疗与健康SBIR的应用源于显示核苷酸结合的重要作用的数据。 寡聚化结构域，富含亮氨酸重复序列的X1（NLRX 1）作为IBD的新治疗靶点。 我们的产品：BTI已经确定了第一个小分子化合物家族， 调节分子NLRX 1。该项目的目标是验证NLRX 1作为目标，并开发NX-13作为目标。 基于NLRX 1的领先口服IBD一流治疗药物。 背景：IBD是一种慢性广泛和使人衰弱的疾病，困扰着全世界超过500万人。 目前的治疗方法只取得了一定的成功，但有明显的不良副作用，包括癌症、感染 与死因此，存在对更安全、更有效的IBD治疗剂的未满足的临床需求。NLRX 1可以 抑制感染和自身免疫性疾病期间的肠道炎症。BTI已经证实， NLRX 1导致粘膜愈合减少，纤维化增加，炎性细胞因子上调>5倍 生物标志物和IBD期间肠道微生物组生态的完全重建。此外，我们的顶级NLRX 1 配体在IBD模型中发挥治疗作用。该SBIR第一阶段应用将表征配体- NX-13和NLRX 1的蛋白质相互作用，定义了NX-13的细胞作用机制，并验证了其 安全性和特异性。具体目标是： AIM 1.通过CD光谱和等温法评估NX-13与纯化的原位NLRX 1的相互作用 通过对纯化的WT和突变体NLRX 1的量热法和细胞热位移测定。 AIM 2.在结肠炎DSS模型中，使用cre-13测定NX-13体内作用的细胞机制。 NLRX 1的lox细胞特异性（CD 4+、骨髓、上皮）敲除。 AIM 3.在脱靶结合试验中使用NX-13进行初步ADME-Tox和特异性试验，7天 大鼠剂量范围探索毒性研究和ADME-Tox试验（hERG、艾姆斯、CYP 450、P-gp）。 预期结果：通过以下方式验证NX-13作为靶向NLRX 1的先导分子：i） 浓度≤ 0.1 µM的原位NLRX 1）; ii）通过在以下方面的疗效丧失鉴定细胞作用机制： 细胞特异性KO小鼠; iii）大鼠经口给药NOAEL ≥ 1，000 mg/kg的良性安全性特征。 SBIR II期将验证NLRX 1在人IBD中的意义，确定大鼠中的PK，确定抗纤维化 在小鼠肠纤维化模型中的作用，并将NX-13推进到IND使能GLP毒理学研究。 商业应用：该项目的成功将启动以BTI为中心的新药开发管道。 对具有抗炎和抗纤维化作用的NLRX 1活化治疗剂的作用。BTI的新NLRX 1-靶向 口腔治疗可能会扰乱每年以25%的年增长率超过100亿美元的市场。