Immunometabolic NLRX1 Therapeutics for IBD

免疫代谢药物NLRX1治疗IBD 生物治疗公司(BTI)是一家新兴的生物技术公司，它协同结合了先进的 采用平移实验的计算建模加速新产品的开发 精准医疗与健康。这种SBIR应用源于显示核苷酸结合的重要作用的数据 低聚结构域，富含亮氨酸重复序列的X1(NLRX1)作为IBD治疗的新靶点。 我们的产品：BTI已经确定了第一个结合并激活该小说的小分子化合物家族 调控分子NLRX1。该项目的目标是验证NLRX1作为目标，并将NX-13开发为 领导基于NLRX1的IBD口服一流治疗。 背景：IBD是一种慢性、广泛性和衰弱的疾病，困扰着全球500多万人。 目前的治疗只取得了一定的成功，并有严重的副作用，包括癌症、感染 和死亡。因此，临床上对更安全、更有效的IBD疗法的需求尚未得到满足。NLRX1可以 抑制感染和自身免疫性疾病期间的肠道炎症。BTI已确认这一损失 NLRX1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，以及IBD期间肠道微生物生态的完全重建。此外，我们的顶级NLRX1 配体在IBD模型中发挥治疗作用。这一SBIR第一阶段应用将表征配体- NX-13和NLRX1的蛋白质相互作用，确定NX-13细胞的作用机制并验证其 NLRX1的安全性和特异性。具体目标是： 目的1.用圆二色谱和等温法研究NX-13与纯化的和原位的NLRX1的相互作用 纯化的WT和突变体NLRX1的量热法和细胞热位移分析。 目的2.用cre-13研究NX-13在DSS结肠炎模型中的细胞作用机制。 LOX细胞特异性(CD4+、髓系、上皮)NLRX1基因敲除。 目的3.用NX-13进行初步的ADME-Tox和特异性的脱靶结合分析，7-d 对大鼠的剂量范围毒性研究和ADME-Tox分析(HERG，Ames，CyP450，P-gp)。 预期结果：确认NX-13为靶向NLRX1的先导分子：i)参与 NLRX1在原位浓度≤0.1uM)；ii)通过在细胞中失去效力来鉴定作用机制 细胞特异性KO小鼠；iii)大鼠口服NOAEL≥1,000 mg/kg的良性安全概况。 SBIR第二阶段将验证NLRX1在人IBD中的意义，测定大鼠的PK，定义抗纤维化 对小鼠肠纤维化模型的影响以及NX-13对IND-Enabling GLP毒理学研究的进展。 商业应用：该项目的成功将在BTI中心启动一条新药开发管道 具有抗炎和抗纤维化作用的NLRX1激活疗法的研究。BTI的新NLRX1-目标 口腔治疗药物可能会扰乱这个每年超过100亿美元、以每年25%的速度增长的市场。

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.