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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要克罗恩病 (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、疼痛和体重减轻的 CD 影响了多达 100 万美国人，是 CD 的一种。 CD 是由 CD4 T 细胞驱动的，对 TH1 和 TH17 细胞起着重要作用 B 细胞的额外参与目前的 CD 疗法可能有效，但原发率较高。和继发性失败，并与显着且有时严重的副作用相关。需要有效的疗法来治疗CD。脱氧核糖核苷挽救途径具有限速酶。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可以使用 PET 放射性示踪剂在小鼠和人类体内非侵入性地测量 dCK 活性。在多种临床前模型中，淋巴细胞中的 [18F]FAC 和 [18F]CFA 活性分别上调。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。 Trethera 最近分析的一个时间点，小鼠结肠炎模型中的脾脏活性上调。开发了 TRE-515 作为一种有效的、选择性的小分子 dCK 抑制剂，具有优异的体内药代动力学 TRE-515 最近获得 FDA 批准（IND# 131939）进行研究。用于治疗实体瘤，并已在 I 期临床中对多名患者安全给药我们最近在多个实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中进行了试验。疾病期间淋巴细胞中的 dCK 活性上调，TRE-515 可以限制淋巴细胞中的 dCK 活性在体内组织中，TRE-515 可以阻止这些 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 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 直接阻断培养中的 T 细胞增殖 MS 和 CD 是不同的疾病，但具有相同的激活和激活状态。 TH1 和 TH17 CD4 T 细胞增殖是疾病的常见驱动因素，我们勇敢地承认 TRE-515 可能是疾病的驱动因素。我们将通过第一阶段 STTR 拨款开始测试这一假设。目标 1：量化疾病期间淋巴器官和肠道中的 dCK 活性。过继转移和 SAMP1/YitFc CD 模型目标 2：测试 dCK 抑制剂 TRE-515 是否可以阻断疾病。临床前 CD 模型的进展。