Validation of Immunometabolic NLRX1 Therapeutics for IBD

IBD 免疫代谢 NLRX1 疗法的验证

• 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
• 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

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免疫代谢NLRX 1治疗药物的验证 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。在I期SBIR中，我们成功地将NX-13确定为NLRX 1特异性激动剂， 在CD 4 + T细胞特异性免疫代谢机制中，炎症病变减少90%。 背景：IBD是一种慢性、广泛和使人衰弱的疾病，困扰着全世界500多万人 仅在美国，每年的总支出就超过150亿美元。目前的治疗方法只是适度的 但有严重的副作用。因此，存在对更安全、更有效、更安全的药物组合物的未满足的临床需求。 IBD治疗。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的缺失导致粘膜愈合减少，纤维化增加， 炎症细胞因子生物标志物和IBD期间肠道微生物组生态的完全重建。该SBIR II期申请将表征NX-13的微生物和抗纤维化机制，证明 在人UC原代细胞中的转化效力，并进行IND使能安全性研究。 具体目标是： AIM 1.通过16 S肠道确定NX-13对结肠炎期间肠道微生物组的影响 微生物组测序和肠道微生物组相互作用的特征。 AIM 2.表征NX-13在慢性结肠炎模型中的抗纤维化机制和对结肠炎的体外作用。 成纤维细胞基因表达和细胞外基质沉积。 AIM 3.通过以下方法验证NX-13在来自UC患者的PBMC和LPMC中的转化功效： 评价总体细胞应答和CD 4特异性免疫代谢机制。 AIM 4.在非啮齿类动物种属中进行28天重复给药的IND使能GLP毒性研究 在三个剂量水平（250、500、1000 mg/kg）下与媒介物相比的毒性研究。 预期结果：通过以下方式验证NX-13作为靶向NLRX 1的主要激动性分子： NX-13肠道微生物和抗纤维化机制鉴定; ii）TNFα和IFNγ减少50% 在人PBMC和LPMC中产生;和iii）口服NOAEL ≥ 1，000 mg/kg的良性安全性特征。 商业应用：该项目的成功将启动一个以 具有抗炎和抗纤维化作用的NLRX 1活化治疗剂。BTI的新NLRX靶向口服 治疗可能会扰乱每年以25%的年增长率增长超过100亿美元的市场。