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

项目总结 克罗恩病(CD)是一种慢性自身免疫性疾病，免疫系统的细胞攻击肠道组织 导致腹泻、疲劳、疼痛和体重减轻。CD影响着多达一百万的美国人，是一种 炎症性肠病。CD由CD4T细胞驱动，对TH1和TH17细胞起重要作用 B细胞的额外参与。目前对CD的治疗方法是有效的，但原发率较高。 和继发性失败，并与显著的、有时严重的副作用有关。新的保险箱和 治疗CD需要有效的治疗方法。限速酶作用下的脱氧核糖核苷挽救途径 脱氧胞苷酸激酶(DCK)回收胞外脱氧核糖核苷为胞内脱氧核苷酸 新陈代谢。使用PET放射性示踪剂可以在小鼠和人类体内无创地测量DCK活性 [18F]FAC和[18F]CFA。在多种临床前模型中，DCK活性在淋巴细胞中上调 自身免疫性疾病，包括自身免疫性肝炎和多发性硬化症。一项研究表明，DCK 在小鼠结肠炎模型中，在分析的一个时间点，脾的活性被上调。特雷瑟拉最近 开发出一种高效、选择性的小分子DCK抑制剂Tre-515，具有良好的体内药代动力学 和药效学特性。TRE-515最近被食品和药物管理局批准(IND#131939)进行研究 用于实体肿瘤的治疗，已安全地用于I期临床的多名患者 审判。我们最近在多个实验性自身免疫性脑脊髓炎(EAE)小鼠模型中展示了MS 疾病时淋巴细胞中DCK活性上调，TRE-515可限制淋巴中DCK活性 在体内组织中，TrE-515可以阻断这些EAE小鼠模型的临床MS症状 在疾病诱导或症状出现时，tre-515通过阻断这些模型来限制疾病。 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-Tre- 515直接阻断培养中T细胞的增殖。MS和CD是不同的疾病，但共同激活和 TH1和TH17CD4T细胞的增殖是疾病的共同驱动因素。我们推测Tre-515可能是 一种治疗CD的有效方法。我们将开始在第一阶段STTR拨款中测试这一假设，方法是 遵循两个目标。目的1：定量DCK在淋巴器官和肠道中的活性。 采用转移和SAMP1/YitFc CD模型。目的2：检测DCK抑制剂tre-515能否阻断疾病 临床前CD模型的进展。

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.