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）是一种急性自身免疫性疾病，由对保护视神经的髓鞘的免疫攻击引起。 导致视力丧失的视神经。类固醇治疗可以加速一些患者视力的恢复， 对其他视觉功能没有影响，例如对日常生活活动很重要的对比敏感度。 即使使用类固醇治疗，每年仍有13，000名ON患者无法完全恢复视力，50%的ON患者无法完全恢复视力。 患者最终会转变为多发性硬化症。需要新的疗法来改善ON患者的结局， 生活质量T和B淋巴细胞的异常活化驱动ON病理。针对这些致病 细胞是一种潜在的治疗策略。我们的公司Trethera已经进行了广泛的临床前研究， 开发一种小分子药物TRE-515，它有可能选择性地阻断ON中的淋巴细胞活化。 通过抑制脱氧胞苷激酶（dCK），脱氧核糖核苷补救途径中的关键限速酶。 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都会激活dCK， ON C57 B1/6 MOG 35 -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阻断免疫细胞中CNS脱髓鞘的表型， （iv）TRE-515阻断该模型中的视神经炎症，（v）TRE-515阻断T细胞增殖， （vi）TRE-515阻断该模型中的B和T细胞活化，和（vii）TRE-515 治疗和dCK敲除与显著毒性无关。总的来说，这些数据有力地 表明TRE-515可能是ON的一种重要的新疗法。为了支持这一点，FDA最近授予 TRE-515 ON的孤儿药状态。在拟议的快速通道项目中，我们将进行关键的临床前 证实TRE-515作为ON疗法的安全性的研究，研究 TRE-515影响，以确定适当的给药方案，并确定靶点的潜在生物标志物。 订婚在第一阶段，我们将研究TRE-515治疗性给药是否可以阻断ON症状 (Aim目的2：评价TRE-515的遗传毒性。在第二阶段，我们将研究剂量反应， TRE-515和ON症状在ON的MOG 35 -55 EAE小鼠模型中的关系（目的3），评估 TRE-515在另一个ON模型中的作用（目的4），研究TRE-515阻断的机制 淋巴细胞增殖（目的5），并评估血浆脱氧胞苷和脱氧尿苷水平是否可以 作为TRE-515靶向结合的生物标志物（目的6）。这一IND使能工作将是至关重要的， TRE-515用于临床ON患者和设计成功率最高的临床试验。