Immunoregulatory Therapeutics for Ulcerative Colitis

溃疡性结肠炎的免疫调节治疗

• 批准号: 10697464
• 负责人: Andrew Leber
• 金额: $ 35.61万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697464
• 关键词: ABCB1 gene; Acceleration; Address; Adoptive Transfer; Adverse effects; Affect; Aftercare; American; Binding; Biological Assay; Biological Response Modifier Therapy; Biotechnology; CD4 Positive T Lymphocytes; Cells; Chemicals; Chronic; Clinical; Clinical Trials; Colitis; Colon; Computer Models; Crohn' s disease; Development; Digestive System Disorders; Disease; Disease remission; Dose; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Family; Flow Cytometry; Foundations; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Genetic Transcription; Goals; Histologic; Histopathology; Human; IL18 gene; Immunology procedure; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injections; Interferon Type II; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-15; Interleukin-2; Intestinal Mucosa; Lamina Propria; Large Intestinal Mucosa; Lead; Link; Macrophage; Marketing; Measures; Medical; Medical Care Costs; Membrane; Mendelian randomization; Modeling; Mus; Oral; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Precision Health; Prevention; Production; Proliferating; Rattus; Role; Sampling; Signal Transduction; Small Business Innovation Research Grant; Specificity; Target Populations; Technology; Th1 Cells; Therapeutic; Treatment Efficacy; Ulcerative Colitis; United States; Up-Regulation; commercial application; commercialization; cytokine; design; dextran sulfate sodium induced colitis; drug metabolism; effective therapy; efficacy validation; immune modulating agents; immunoregulation; in vivo; indexing; inhibitor; interleukin-23; intestinal epithelium; meter; monocyte; mouse model; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient population; pharmacologic; precision medicine; prototype; public health relevance; receptor; response; safety study; scaffold; side effect; standard of care; success; therapeutic target; therapeutically effective; translational applications

Immunoregulatory Therapeutics for Ulcerative Colitis 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. Inflammatory bowel disease (IBD) is a chronic and disabling inflammatory disease of the gastrointestinal tract that afflicts 2 million Americans and over 5 million people worldwide. Current therapeutics are unsuccessful in maintaining remission and have been linked to serious side effects. BTI recently uncovered a novel chemical family that inhibits IL-18, an inflammatory cytokine produced by epithelial cells of the gastrointestinal tract to activate differentiation of IFNγ-producing Th1 cells and polarization of inflammatory macrophages. Our prototype NCE significantly reduced colonic scores and Th1 in the colonic lamina propria after DSS challenge and in the spontaneous Mdr1a-/- model of colitis, consistent with the proposed IL-18-blocking mechanism. This project will further characterize mechanisms of IL-18 signaling in IBD and validate the therapeutic efficacy of IL-18 inhibition in vivo and in human primary cells. The Specific Aims for this SBIR Phase I application are to: AIM 1. Evaluate the relative therapeutic efficacy of IL-18 inhibitors in vitro. We will assess the potency of IL-18 inhibition through binding and functional assays. AIM 2. Determine the therapeutic potential of IL-18 inhibition in mouse models of IBD. We will use the CD45RBhi adoptive transfer and DSS models of colitis to characterize the in vivo dose response to IL-18 inhibition through histological, transcriptional and immunological assays. AIM 3. Validate the responsiveness of in human UC patient cells to IL-18 signaling and inhibition. We will examine responses of healthy and UC PBMCs and LPMCs to IL-18 exposure and pharmacological inhibition. Expected successful outcomes will include: i) ≥ 50% reduction of IFNγ production in response to IL-18 after treatment in vitro; ii) ≥ 70% reduction of histological scores in adoptive transfer and DSS models of colitis; and iii) ≥ 50% reduction in IFNγ production in human UC PBMCs with IL-18 inhibition. The SBIR Phase II application will determine exposure-response relationships in therapeutic efficacy of IL-18 inhibition in chronic colitis models, conduct pharmacokinetic (PK) and safety studies in rats, evaluate the drug metabolism and off-target effects, and further validate the role of IL-18 as a therapeutic target in human UC and Crohn’s disease (CD). The long-term goal of this project is to develop a novel immunomodulatory therapeutic that is safer and more effective for treating IBD and provide a path towards commercialization of an asset with a target patient population of over 5 million with unmet clinical needs and a growing therapeutic market of $16 billion.

溃疡性结肠炎的免疫调节疗法