Immunometabolic NLRX1 Therapeutics for IBD

IBD 免疫代谢 NLRX1 疗法

基本信息

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
项目类别：
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

项目摘要

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NLRX1治疗剂 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。该项目的目的是将NLRX1验证为目标，并将NX-13作为目标基于NLRX1的铅，基于IBD的口服第一类疗法。背景：IBD是一种慢性广泛和使人衰弱的疾病，在全球范围内遭受了超过500万人的困扰。当前的治疗只有明显的不良副作用，包括癌症，感染，仅是微不足道的。和死亡。这是对更安全，更有效的IBD治疗的未满足的临床需求。 NLRX1可以在感染和自身免疫性疾病期间抑制肠道注射。 BTI已验证了损失 NLRX1导致粘膜愈合降低，纤维化增加，炎症细胞因子的上调> 5倍 IBD期间的生物标志物和肠道微生物组生态的完整恢复。此外，我们的顶级NLRX1 配体在IBD模型中执行热动作。 SBIR I期应用将表征配体 - NX-13和NLRX1的蛋白质相互作用，定义了NX-13细胞作用机理并验证其 NLRX1的安全性和特异性。具体目的是： AIM 1。通过CD谱图和等温评估NX-13与纯化和原位NLRX1的相互作用纯化的WT和突变型NLRX1以及通过细胞热移测定法上的量热法。 AIM 2。使用CRE-确定体内NX-13在体内的细胞作用机理 NLRX1的LOX细胞特异性（CD4+，髓样，上皮）敲除。 AIM 3。在脱靶结合测定中使用NX-13进行初步ADME-TOX和特异性测定，7-D 剂量范围发现大鼠和ADME-TOX分析（HERG，AMES，CYP450，P-gp）的毒性研究。预期结果：验证NX-13作为靶向NLRX1的铅分子：i）参与 NLRX1原位浓度≤0.1µm）; ii）鉴定通过失去效率的细胞作用机理细胞特异性KO小鼠； iii）良性安全性，大鼠的Noael≥1,000mg/kg口服。 SBIR II期将验证NLRX1在人IBD中的含义，确定大鼠的PK，定义抗纤维化在肠纤维化的小鼠模型中的影响，并将NX-13提高到了GLP毒理学研究。商业应用：该项目的成功将在BTI中心推出新的药物开发管道在具有抗炎和抗纤维化作用的NLRX1激活疗法上。 BTI的新NLRX1靶向口服疗法每年以25％的年率增长10B美元以上的市场。