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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要视神经炎 (ON) 是一种急性自身免疫性疾病，由免疫攻击保护视神经的髓磷脂引起。视神经导致视力丧失。类固醇治疗可加速某些患者视力的恢复，但对日常生活活动重要的其他视觉功能（例如对比敏感度）没有影响。即使采用类固醇治疗，每年仍有 13,000 名视神经病患者未能完全恢复视力，其中 50% 的视神经病患者无法完全恢复视力患者最终转化为多发性硬化症。需要新的疗法来改善 ON 患者的治疗结果生活质量。 T 和 B 淋巴细胞的异常激活会导致 ON 病变。针对这些致病菌细胞是一种潜在的治疗策略。我们公司 Trethera 进行了广泛的临床前研究开发一种小分子药物 TRE-515，具有选择性阻断 ON 淋巴细胞激活的潜力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) 在疾病的所有阶段，免疫系统细胞都会激活 dCK ON 的 C57Bl/6 MOG35-55 实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型，(ii) TRE-515 阻断该模型中免疫细胞中的 dCK 活性，(iii) TRE-515 阻断中枢神经系统脱髓鞘的表型该模型，(iv) TRE-515 阻断该模型中的视神经炎症，(v) TRE-515 阻断 T 细胞培养物中的激活，(vi) TRE-515 阻断该模型中的 B 细胞和 T 细胞激活，以及 (vii) TRE-515 治疗和 dCK 敲除与显着毒性无关。总的来说，这些数据强烈表明 TRE-515 可能成为治疗 ON 的重要新疗法。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研究研究确认 TRE-515 作为治疗 ON 的安全性，研究 ON 疾病阶段 TRE-515影响，确定适当的剂量方案，并确定目标的潜在生物标志物订婚。在第一阶段，我们将研究 TRE-515 治疗是否可以阻止 ON 症状（目标 1）并评估 TRE-515 的遗传毒性（目标 2）。在第二阶段，我们将检查剂量反应 MOG35-55 EAE 小鼠 ON 模型中 TRE-515 与 ON 症状之间的关系（目标 3），评估 TRE-515 在另一个 ON 模型中的作用（目标 4），研究 TRE-515 阻断的机制淋巴细胞增殖（目标 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 目标参与的生物标志物（目标 6）。这项支持 IND 的工作对于推动 TRE-515进入针对ON患者的临床并设计成功机会最高的临床试验。