Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Optic Neuritis

开发一种新型核苷挽救途径靶向小分子抑制剂来治疗视神经炎

• 批准号: 10543941
• 负责人: Kenneth Schultz
• 金额: $ 36.82万
• 依托单位: TRETHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543941
• 关键词: Activated Lymphocyte; Acute; Affect; Area Under Curve; Autoantigens; Autoimmune Diseases; Award; B-Cell Activation; B-Lymphocytes; Biological Markers; Blindness; Blood; Cells; Clinical; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Consumption; Contrast Sensitivity; DNA; Data; Defect; Demyelinations; Deoxycytidine; Deoxycytidine Kinase; Deoxyribonucleosides; Deoxyuridine; Development; Disease; Dose; Drug Targeting; Ensure; Enzymes; Experimental Autoimmune Encephalomyelitis; Eye; Frequencies; Histologic; Histology; Histopathology; Human; Image; Immune; Immune system; Infiltration; Inflammation; Knock-out; Leukocytes; Life; Lymphocyte; Lymphocyte Activation; Measures; Methylprednisolone; Micronucleus Tests; Modeling; Multiple Sclerosis; Mus; Myelin; Optic Nerve; Optic Neuritis; Orphan Drugs; Outcome; Pathogenicity; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Plasma; Positron-Emission Tomography; Preclinical Testing; Property; Quality of life; Recovery; Regimen; Retinal Ganglion Cells; Safety; Spleen; Standard Model; Steroids; Study models; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transgenic Organisms; Treatment outcome; Vision; Visual; Visual Acuity; Work; autoreactive T cell; cell injury; clinical phenotype; dosage; genotoxicity; improved; in vivo; in vivo monitoring; inhibitor; lymph nodes; lymphocyte proliferation; mouse model; novel; novel therapeutics; nucleoside inhibitor; potential biomarker; pre-clinical; preclinical study; radiotracer; replication stress; response; side effect; small molecule; small molecule inhibitor; standard of care; success; targeted biomarker; tripolyphosphate

PROJECT SUMMARY Optic neuritis (ON) is an acute autoimmune disease caused by immune attack on the myelin that protects the optic nerve leading to vision loss. Steroid treatments accelerate recovery of visual acuity in some patients but have no effect on other visual functions such as contrast sensitivity that are important for activities of daily life. Even with steroid treatments, 13,000 ON patients per year fail to fully recover visual acuity and 50% of ON patients eventually convert to multiple sclerosis. New therapies are needed to improve ON patient outcomes and quality-of-life. Aberrant activation of T and B lymphocytes drives ON pathologies. Targeting these pathogenic cells is a potential therapeutic strategy. Our company, Trethera, has conducted extensive preclinical studies to develop a small molecule drug, TRE-515, that has the potential to selectively block lymphocyte activation in ON by inhibiting deoxycytidine kinase (dCK), a key rate-limiting enzyme in the deoxyribonucleoside salvage pathway. Our preliminary studies show (i) that cells of the immune system activate dCK during all phases of disease in the C57Bl/6 MOG35-55 experimental autoimmune encephalomyelitis (EAE) mouse model of ON, (ii) that TRE-515 blocks dCK activity in immune cells in this model, (iii) that TRE-515 blocks phenotypes of CNS demyelination in this model, (iv) that TRE-515 blocks inflammation of the optic nerve in this model, (v) that TRE-515 blocks T cell activation in culture, (vi) that TRE-515 blocks B and T cell activation in this model, and (vii) that TRE-515 treatments and dCK knockout are not associated with significant toxicities. Collectively, these data strongly suggest that TRE-515 could be an important new therapy for ON. In support of this, the FDA recently awarded TRE-515 Orphan Drug Status for ON. In the proposed Fast-Track project, we will conduct critical preclinical studies to confirm the safety properties of TRE-515 as a therapy for ON, to study the ON disease stage that TRE-515 affects, to identify the appropriate dosage regimen, and to identify potential biomarkers of target engagement. In Phase I, we will study whether TRE-515 administered therapeutically can block ON symptoms (Aim 1) and evaluate the genotoxicity of TRE-515 (Aim 2). In Phase II, we will examine the dose-response relationship between TRE-515 and ON symptoms in the MOG35-55 EAE mouse model of ON (Aim 3), evaluate the effect of TRE-515 in an additional ON model (Aim 4), study the mechanisms through which TRE-515 blocks lymphocyte proliferation (Aim 5), and evaluate whether plasma deoxycytidine and deoxyuridine levels could serve as biomarkers of TRE-515 target engagement (Aim 6). This IND-enabling work will be critical for moving TRE-515 into the clinical for ON patients and for designing clinical trials with the highest chance of success.

项目摘要 视神经炎（ON）是由免疫攻击对髓磷脂引起的急性自身免疫性疾病，可保护该疾病 视神经导致视力丧失。类固醇治疗加速某些患者的视力恢复，但 对其他视觉功能没有影响，例如对比敏感性，这对于日常生活的活动很重要。 即使接受类固醇治疗，患者每年也无法完全恢复视力，而50％ 患者最终转化为多发性硬化症。需要新的疗法来改善患者预后和 生活质量。 T和B淋巴细胞的异常激活在病理上驱动。针对这些病原体 细胞是一种潜在的治疗策略。我们的公司Trethera已进行了广泛的临床前研究 开发一种小分子药物TRE-515，具有选择性地阻断淋巴细胞活化的潜力 通过抑制脱氧胞苷激酶（DCK），这是脱氧核糖核苷拯救途径中的一种限制率的酶。 我们的初步研究表明（i），免疫系统的细胞在疾病的所有阶段激活DCK C57BL/6 MOG35-55实验性自身免疫性脑脊髓炎（EAE）小鼠模型，（ii）TRE-515 在该模型中阻断免疫细胞中的DCK活性，（iii）TRE-515阻止了中枢神经系统脱髓鞘的表型 该模型（iv）TRE-515阻塞了该模型中视神经的炎症，（v）TRE-515阻止T细胞 培养中的激活，（vi）TRE-515阻止了该模型中B和T细胞激活，并且（vii）TRE-515 治疗和DCK敲除与明显的毒性无关。总的来说，这些数据强烈 表明TRE-515可能是重要的新疗法。为此，FDA最近授予 TRE-515 ON的孤儿药物状态。在拟议的快速轨道项目中，我们将进行关键的临床前 研究确认TRE-515作为ON的安全性，以研究疾病阶段的疗法 TRE-515会影响，确定适当的剂量方案并确定靶标的潜在生物标志物 订婚。在第一阶段，我们将研究TRE-515是否可以通过治疗进行治疗 （AIM 1）并评估TRE-515的遗传毒性（AIM 2）。在第二阶段，我们将检查剂量反应 TRE-515与MOG35-55 EA鼠标模型（AIM 3）中的症状之间的关系，评估 TRE-515在额外模型中的影响（AIM 4），研究TRE-515块的机制 淋巴细胞增殖（AIM 5），并评估血浆脱氧胞苷和脱氧尿苷水平是否可以 用作TRE-515目标参与的生物标志物（AIM 6）。这项成熟的工作对于移动至关重要 TRE-515进入患者的临床和设计成功机会最高的临床试验。