Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Crohn's disease

开发一种新型核苷挽救途径靶向小分子抑制剂来治疗克罗恩病

• 批准号: 10820782
• 负责人: Kenneth Schultz
• 金额: $ 39.51万
• 依托单位: TRETHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10820782
• 关键词: Abdominal Pain; Adoptive Transfer; Adverse event; Affect; American; Ames Assay; Antibodies; Antigen Targeting; Autoimmune Diseases; Autoimmune Hepatitis; B Cell Proliferation; B-Lymphocytes; Biological Markers; Body Weight decreased; CD4 Positive T Lymphocytes; Cancer Patient; Cells; Central Nervous System; Chronic; Cladribine; Clinical; Crohn' s disease; DNA biosynthesis; Data; Deoxycytidine; Deoxycytidine Kinase; Deoxyribonucleosides; Deoxyribonucleotides; Development; Diarrhea; Disease; Disease Progression; Disease model; Disease remission; Dose; Drug Targeting; Enzyme Inhibitor Drugs; Enzymes; Experimental Autoimmune Encephalomyelitis; Failure; Fatigue; Grant; Histologic; Human; Immune; Immune system; Infection; Inflammation; Inflammatory Bowel Diseases; Lead; Length; Link; Lymphocyte; Lymphocyte Activation; Lymphoid Cell; Lymphoid Tissue; Macrophage; Malignant Neoplasms; Measurable; Measures; Metabolism; Modeling; Multiple Sclerosis; Mus; Onset of illness; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Proliferating; Property; Publishing; Regulatory T-Lymphocyte; Relapse; Risk; Role; Serious Adverse Event; Small Business Technology Transfer Research; Solid Neoplasm; Spleen; Symptoms; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Tissues; Up-Regulation; Weight; Work; autoreactive B cell; autoreactivity; cell type; chronic autoimmune disease; effective therapy; extracellular; gut inflammation; immune cell infiltrate; improved; in vivo; infliximab; insight; kinase inhibitor; lymph nodes; lymphoid organ; mouse model; murine colitis; novel; novel therapeutics; nucleoside inhibitor; pharmacokinetics and pharmacodynamics; phase 2 study; pre-clinical; prophylactic; radiotracer; research clinical testing; side effect; small molecule; small molecule inhibitor; success

PROJECT SUMMARY Crohn’s disease (CD) is a chronic autoimmune disease in which cells of the immune system attack gut tissue leading to diarrhea, fatigue, pain, and weight loss. CD affects up to one million Americans and is a type of inflammatory bowel disease. CD is driven by CD4 T cells with a significant role for TH1 and TH17 cells and additional involvement of B cells. Current therapies for CD can be effective but suffer from high rates of primary and secondary failure and are associated with significant and sometimes severe side effects. New safe and effective therapies are needed to treat CD. The deoxyribonucleoside salvage pathway with rate-limiting enzyme deoxycytidine kinase (dCK) salvages extracellular deoxyribonucleosides for intracellular deoxyribonucleotide metabolism. dCK activity can be measured non-invasively in vivo in mice and humans using the PET radiotracers [18F]FAC and [18F]CFA, respectively. dCK activity is upregulated in lymphocytes in multiple preclinical models of autoimmune diseases including autoimmune hepatitis and multiple sclerosis (MS). One study showed that dCK activity is upregulated in the spleen in a mouse colitis model at the one time-point analyzed. Trethera has recently developed TRE-515 as a potent and selective small molecule dCK inhibitor with excellent in vivo pharmacokinetic and pharmacodynamic properties. TRE-515 was recently cleared by the FDA (IND# 131939) for investigational use in the treatment of solid tumors and has been safely administered to multiple patients in Phase I clinical trials. We recently showed in multiple experimental autoimmune encephalomyelitis (EAE) mouse models of MS that dCK activity is upregulated in lymphocytes during disease, that TRE-515 can limit dCK activity in lymphoid tissues in vivo, that TRE-515 can block clinical MS symptoms in these EAE mouse models when treatments are initiated at disease induction or at symptoms onset, that TRE-515 limits disease in these models by blocking activation-induced T and B cell proliferation without affecting other cells in the immune system, and that TRE- 515 directly blocks T cell proliferation in culture. MS and CD are different diseases but share activated and proliferating TH1 and TH17 CD4 T cells as a common driver of disease. We hypothesize that TRE-515 could be an effective treatment for CD. We will begin to test this hypothesis in this Phase I STTR grant through the following two aims. Aim 1: To quantify dCK activity in the lymphoid organs and gut throughout disease in the adoptive transfer and SAMP1/YitFc CD models. Aim 2: To test whether the dCK inhibitor TRE-515 blocks disease progression in a preclinical CD model.

项目摘要 克罗恩病（CD）是一种慢性自身免疫性疾病，其中免疫系统细胞攻击肠道组织 导致腹泻疲劳疼痛和体重减轻CD影响多达100万美国人，是一种 炎症性肠病CD由CD 4 T细胞驱动，对TH 1和TH 17细胞具有重要作用， B细胞的额外参与。目前CD的治疗方法可能有效，但原发性 和二次失败，并与显著的，有时是严重的副作用有关。新的安全和 需要有效的疗法来治疗CD。具有限速酶的脱氧核苷补救途径 脱氧胞苷激酶（dCK）将细胞外脱氧核糖核苷转化为细胞内脱氧核糖核苷酸 新陈代谢. dCK活性可以使用PET放射性示踪剂在小鼠和人体内非侵入性地测量 [18F]FAC和[18F]CFA。在多个临床前模型中，淋巴细胞中dCK活性上调 自身免疫性疾病，包括自身免疫性肝炎和多发性硬化症（MS）。一项研究表明，dCK 在所分析的一个时间点，小鼠结肠炎模型的脾脏中的活性上调。Trethera最近在 开发TRE-515作为一种有效的和选择性的小分子dCK抑制剂，具有良好的体内药代动力学 和药效学特性。TRE-515最近被FDA批准（IND# 131939）用于研究 用于治疗实体瘤，并已在I期临床试验中安全地用于多名患者 审判我们最近在多个实验性自身免疫性脑脊髓炎（EAE）小鼠MS模型中发现， 疾病期间淋巴细胞中dCK活性上调，TRE-515可限制淋巴细胞中dCK活性， 在体内组织中，TRE-515可以阻断这些EAE小鼠模型中的临床MS症状， TRE-515在疾病诱导或症状出现时启动，通过阻断来限制这些模型中的疾病 激活诱导的T和B细胞增殖，而不影响免疫系统中的其他细胞，并且TRE- 515直接阻断培养物中的T细胞增殖。MS和CD是不同的疾病，但共享激活和 增殖TH 1和TH 17 CD 4 T细胞作为疾病的共同驱动因素。我们假设TRE-515可能是 CD的有效治疗。我们将开始在第一阶段STTR拨款中测试这一假设， 遵循两个目标。目的1：量化在整个疾病中淋巴器官和肠道中的dCK活性， 过继转移和SAMP 1/YitFc CD模型。目的2：测试dCK抑制剂TRE-515是否阻断疾病 在临床前CD模型中的进展。