Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleoside Salvage Pathway to Treat Acute Disseminated Encephalomyelitis (ADEM)

开发一种新型核苷挽救途径靶向小分子抑制剂来治疗急性播散性脑脊髓炎 (ADEM)

• 批准号: 10755864
• 负责人: Kenneth Schultz
• 金额: $ 30.45万
• 依托单位: TRETHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755864
• 关键词: 8 year old; Activated Lymphocyte; Acute; Acute Disseminated Encephalomyelitis; Address; Adolescence; Adolescent; Adrenal Cortex Hormones; Adult; Adverse effects; Adverse event; Affect; Age; Antigens; Ataxia; Autoimmune Diseases; Award; B Cell Proliferation; B-Cell Activation; B-Lymphocytes; Behavioral; Bone Marrow; CD4 Positive T Lymphocytes; Cancer Patient; Cells; Central Nervous System; Cessation of life; Child; Clinic; Clinical; Clinical Trials Design; Coma; Complete Blood Count; Cytometry; DNA biosynthesis; Data; Defect; Deoxycytidine; Deoxycytidine Kinase; Deoxyribonucleosides; Deoxyribonucleotides; Development; Dexamethasone; Disease; Dose; Drug Evaluation; Drug Targeting; Drug usage; Enzymes; Event; Experimental Autoimmune Encephalomyelitis; FDA approved; Fever; Gene Mutation; Grant; Human; Hypotension; Immune; Immune system; Immunization; Infection; Intravenous; Knock-out; Lead; Lymphocyte; Measures; Mediating; Medical; Modeling; Morbidity - disease rate; Mus; Myelin; Orphan Drugs; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Population; Positron-Emission Tomography; Prognosis; Rare Diseases; Recovery; Regulatory T-Lymphocyte; Serious Adverse Event; Small Business Technology Transfer Research; Solid Neoplasm; Spleen; Steroids; Symptoms; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Tachycardia; Testing; Therapeutic; Thymus Gland; Time; Toxic effect; Unconscious State; Virus Diseases; Work; autoreactive T cell; cancer therapy; cell type; dosage; immune cell infiltrate; improved outcome; in vivo; kinase inhibitor; lymph nodes; lymphocyte proliferation; mortality; mouse model; novel; novel therapeutics; nucleoside inhibitor; potential biomarker; pre-clinical; preclinical study; prophylactic; radiotracer; side effect; small molecule; small molecule inhibitor; standard of care; success; symptomatic improvement

PROJECT SUMMARY Acute disseminated encephalomyelitis (ADEM) is an acute autoimmune disease that can present with fever and ataxia as well as loss of consciousness and coma. ADEM largely affects children, is driven by T and B lymphocytes aberrantly activated against a myelin antigen, and is strongly associated with a prior infection or immunization. There is no FDA-approved therapy for the treatment of ADEM, and most cases of ADEM are treated with corticosteroids. Corticosteroids have significant side effects, including behavioral changes, hypotension, and tachycardia, and fail to address the significant morbidity and mortality associated with ADEM. Up to 50% of treated ADEM patients fail to fully recover from the disease, and ADEM has a 5 – 10% mortality rate. Our company, Trethera, has developed a small molecule drug, TRE-515, that has the potential to selectively block lymphocyte proliferation in ADEM by inhibiting deoxycytidine kinase (dCK), a key enzyme in the deoxyribonucleoside salvage pathway. Our preliminary studies show in the MOG35-55 experimental autoimmune encephalomyelitis (EAE) mouse model of ADEM that (i) immune cells activate dCK during disease, (ii) TRE-515 blocks dCK activity in immune cells, (iii) prophylactic or therapeutic TRE-515 treatments block clinical symptoms, (iv) TRE-515 treatments lead to fewer immune cell infiltrates in the central nervous system, (v) TRE-515 blocks B and T cell proliferation without affecting other immune cell types including innate immune cells or regulatory T and B cells, (vi) TRE-515 increases plasma deoxycytidine levels suggesting a potential biomarker for evaluation of drug-target engagement, (vii) TRE-515 blocks T cell proliferation in culture, and (viii) TRE-515 treatments and dCK knockout are not associated with significant toxicities. Based on these preclinical studies and due to its status as a rare disease, the FDA recently awarded TRE-515 Orphan Drug Designation (ODD) for the treatment of ADEM. This is the first and only time the FDA has awarded an ODD for the treatment of ADEM. Parallel efforts to develop TRE-515 as a cancer therapy have led to a Phase I clinical trial for solid tumors. Data from the trial show TRE-515 treatments are associated with mild side effects and show evidence of efficacy. Collectively, these data strongly suggest that TRE-515 could be an important new therapy for ADEM. In the proposed project, we will conduct critical preclinical studies to evaluate the effect of TRE-515 on immune cell development and determine whether TRE-515 can be combined with corticosteroids for the treatment of the MOG35-55 EAE ADEM mouse model. This work will be critical for moving TRE-515 into the clinic for ADEM patients and for designing clinical trials with the highest chance of success.

项目总结 急性播散性脑脊髓炎(ADEM)是一种急性自身免疫性疾病，可表现为发热和 共济失调以及意识丧失和昏迷。ADEM在很大程度上影响了儿童，由T和B推动 淋巴细胞对髓鞘抗原异常激活，并与既往感染或 免疫接种。目前还没有FDA批准的治疗ADEM的方法，大多数ADEM病例是 用皮质类固醇治疗。皮质类固醇有显著的副作用，包括行为改变， 低血压和心动过速，未能解决与ADEM相关的显著发病率和死亡率。 高达50%的接受治疗的ADEM患者未能完全从疾病中恢复，ADEM的死亡率为5%-10% 费率。我们的Trethera公司已经开发出一种小分子药物tre-515，它有可能选择性地 通过抑制脱氧胞苷酶(DCK)来阻断ADEM的淋巴细胞增殖 脱氧核糖核苷挽救途径。我们的初步研究表明，在MOG35-55实验性自身免疫 脑脊髓炎(EAE)小鼠模型的建立(I)免疫细胞在疾病过程中激活DCK，(Ii)tre-515 阻断免疫细胞中的DCK活性，(Iii)预防性或治疗性TRE-515治疗阻断临床症状， (Iv)tre-515治疗导致中枢神经系统免疫细胞浸润减少；(V)tre-515阻断 B和T细胞增殖而不影响其他免疫细胞类型，包括先天免疫细胞或调节性T细胞 和B细胞，(Vi)tre-515升高血浆脱氧胞苷水平，提示一个潜在的生物标志物用于评估 在药物靶点结合方面，(Vii)tre-515在培养中阻断T细胞的增殖，以及(Viii)tre-515治疗和 DCK基因敲除与显著的毒性无关。基于这些临床前研究，由于其 作为一种罕见疾病，FDA最近授予TRE-515孤儿药物名称(ODD)用于治疗 阿德姆。这是FDA第一次也是唯一一次为ADEM的治疗颁发ODD。并行努力 开发TRE-515作为癌症治疗方法已导致实体肿瘤的I期临床试验。来自试验的数据 表明TRE-515治疗与轻微的副作用相关，并显示出有效性的证据。总而言之， 这些数据有力地表明TRE-515可能是治疗ADEM的一种重要的新疗法。在拟议的项目中， 我们将进行关键的临床前研究，以评估tre-515对免疫细胞发育和 确定TRE-515能否与皮质类固醇联合治疗MOG35-55 EAE Adem 老鼠模型。这项工作对于将tre-515移植到ADEM患者的临床和设计是至关重要的。 成功几率最高的临床试验。