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Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Systemic Lupus Erythematosus

开发一种新型核苷挽救途径靶向小分子抑制剂来治疗系统性红斑狼疮

基本信息

批准号：
10755905
负责人：
Kenneth Schultz
金额：
$ 30.51万
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：
2023-06-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10755905
关键词：
Adverse event Affect Alopecia Ames Assay Arthritis Autoimmune Diseases Autoimmune Hepatitis B Cell Proliferation B-Lymphocytes Biological Markers Blood Urea Nitrogen Brain CD4 Positive T Lymphocytes Cancer Patient Cells Central Nervous System Chronic Clinical DNA biosynthesis Data Deoxycytidine Deoxycytidine Kinase Deoxyribonucleosides Deoxyribonucleotides Dermatitis Development Disease Disease Progression Dose Drug Targeting Enzyme Inhibitor Drugs Enzymes Experimental Autoimmune Encephalomyelitis Fever Flare Glomerulonephritis Grant Human Hydroxychloroquine Image Immune Immune system Impairment Kidney Lead Life Expectancy Link Lung Lupus Lymphocyte Lymphocyte Activation Lymphoid Tissue Malignant Neoplasms Measurable Measurement Measures Metabolism Modeling Morbidity - disease rate Multiple Sclerosis Mus Myocardial Infarction Onset of illness Organ PET/CT scan Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Plasma Positron-Emission Tomography Pre-Clinical Model Proliferating Property Proteinuria Publishing Regulatory T-Lymphocyte Reporting Role Serious Adverse Event Small Business Technology Transfer Research Solid Neoplasm Spleen Stable Disease Stroke Symptoms Systemic Lupus Erythematosus T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Tissues Treatment Efficacy Work anti-dsDNA antibodies autoreactive B cell autoreactivity body system cell type disease heterogeneity effective therapy extracellular immune cell infiltrate in vivo inhibitor lymph nodes lymphadenopathy lymphoid organ mortality mouse model novel novel therapeutics nucleoside inhibitor patient biomarkers patient stratification patient subsets pharmacodynamic biomarker pharmacokinetics and pharmacodynamics phase 2 study pre-clinical prophylactic radiotracer response side effect small molecule small molecule inhibitor success systemic autoimmune disease targeted biomarker

项目摘要

PROJECT SUMMARY Lupus is a chronic, systemic autoimmune disease in which cells of the immune system attack organ systems throughout the body including the kidneys, brain, and lungs and that presents heterogeneously with symptoms that can include fever, arthritis, alopecia, stroke, and heart attack. Lupus is driven by autoreactive B and CD4 T cells with a particular role for TfH and TH17 CD4 T cells. Current therapies for lupus can be effective but only work on a subset of patients, lack biomarkers to resolve the heterogeneity of the disease as it relates to treatment efficacy, and are associated with significant and sometimes severe side effects. New safe and effective therapies are needed to treat lupus. The deoxyribonucleoside salvage pathway with rate-limiting enzyme deoxycytidine (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 lymph nodes in a mouse lupus 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 using [18F]FAC PET, 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 therapeutic efficacy in these models is associated with a measurable increase in plasma deoxycytidine levels, 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 lupus are different diseases but share activated and proliferating CD4 T and B cells as a common driver of disease. We hypothesize that TRE- 515 could be an effective treatment for lupus. We will begin to test this hypothesis in this Phase I STTR grant through two aims. Aim 1: To quantify dCK activity in the lymphoid organs throughout disease using [18F]FAC PET in a preclinical lupus model. Aim 2: To test whether the dCK inhibitor TRE-515 blocks disease progression in a lupus model.

项目摘要狼疮是一种慢性、系统性自身免疫性疾病，免疫系统的细胞攻击器官系统包括肾脏、大脑和肺在内的全身，并表现出不同的症状包括发烧关节炎脱发中风和心脏病狼疮由自身反应性B和CD 4 T驱动 TfH和TH17 CD4 T细胞具有特殊作用。目前治疗狼疮的方法可能有效，但只有对一部分患者进行研究，缺乏生物标志物来解决与治疗相关的疾病异质性疗效，并与显着的，有时是严重的副作用。新的安全有效的疗法是治疗狼疮所必需的以脱氧胞苷为限速酶的脱氧核苷补救途径 (dCK)回收细胞外脱氧核糖核苷用于细胞内脱氧核糖核苷酸代谢。dck活性可以使用PET放射性示踪剂[18 F] FAC和[18 F] CFA在小鼠和人体内非侵入性地测量，分别在多种自身免疫性疾病临床前模型中，淋巴细胞中dCK活性上调包括自身免疫性肝炎和多发性硬化症（MS）。一项研究表明，dCK活性上调，在所分析的一个时间点的小鼠狼疮模型的淋巴结中。Trethera最近开发了 TRE-515作为一种有效的和选择性的小分子dCK抑制剂，具有优异的体内药代动力学，药效学特性TRE-515最近被FDA批准（IND #131939）用于研究用途在治疗实体瘤中，并已在I期临床试验中安全地施用于多名患者。我们最近在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中发现，使用[18 F] FAC PET，疾病期间淋巴细胞中的dCK活性上调，TRE-515可限制dCK 在体内淋巴组织中的活性，TRE-515可以阻断这些EAE小鼠模型中的临床MS症状当在疾病诱导或症状发作时开始治疗时，与血浆脱氧胞苷水平的可测量增加相关，TRE-515限制了这些患者的疾病，通过阻断活化诱导的T和B细胞增殖而不影响免疫系统中的其他细胞，系统，并且TRE-515直接阻断培养物中的T细胞增殖。MS和狼疮是不同的疾病，共享活化和增殖的CD4 T和B细胞作为疾病的共同驱动因素。我们假设TRE- 515可能是治疗狼疮的有效药物我们将开始在第一阶段STTR拨款中检验这一假设通过两个目标。目的1：使用[18 F] FAC定量整个疾病期间淋巴器官中的dCK活性临床前狼疮模型中的PET。目的2：测试dCK抑制剂TRE-515是否阻断疾病进展在狼疮模型中。