SLE Treatment with N-acetylcysteine

N-乙酰半胱氨酸治疗 SLE

• 批准号: 10462621
• 负责人: Michael P McDermott
• 金额: $ 144.73万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462621
• 关键词: Acetaminophen; Acetylcysteine; Address; Affect; Age; Amino Acids; Anti-Inflammatory Agents; Antidotes; Antioxidants; Autoantibodies; Autoimmune Diseases; B-Cell Activation; Biological Markers; CD3 Antigens; CD8B1 gene; Case Study; Cause of Death; Cell Lineage; Cell secretion; Cells; Clinical; Clinical Management; Clinical Trials; Complex; Cyclic AMP; Cysteine; DNA; Death Rate; Development; Disease; Double-Blind Method; Down-Regulation; Dropout; Drops; Drug Prescriptions; Enrollment; Etiology; FOXP3 gene; FRAP1 gene; Fatigue; Feedback; Functional disorder; Generations; Glutathione; Health Food; Human; IL17 gene; IL2RA gene; Immune; Immune System Diseases; Immunologics; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Interferons; Interleukin-4; Intervention; Kidney Diseases; Knowledge; Kynurenine; Life; Liver Failure; Lupus; Mediating; Metabolic; Metabolic Pathway; Methylation; Mitochondria; Multicenter Trials; Mus; Nausea; Nephritis; Nuclear; Oral; Outcome; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Permeability; Persons; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Plasmablast; Production; Proteins; Randomized; Randomized Controlled Clinical Trials; Reduced Glutathione; Regulatory T-Lymphocyte; Research; Research Design; Role; Safety; Sample Size; Signal Transduction Pathway; Sirolimus; Specific qualifier value; System; Systemic Lupus Erythematosus; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Titrations; Toxic effect; Treatment Efficacy; Withdrawal; Woman; Work; biomarker driven; child bearing; clinical efficacy; clinical practice; clinical predictors; clinically relevant; design; disabling symptom; dosage; effective therapy; efficacy evaluation; follow-up; genetic regulatory protein; improved; in vivo; indexing; innovation; intravenous administration; lupus prone mice; metabolome; mortality; novel; open label; phase II trial; placebo controlled study; predict clinical outcome; primary outcome; promoter; reactive oxygen intermediate; sensor; side effect; treatment response

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with mortality still approaching 10% in 5 years. The leading cause of death in SLE are infections due to the toxicity of immunosuppressant medications. Therefore, a significant unmet need exists for effective and non-toxic medications to treat SLE. Our central hypothesis has been formulated on the basis that effective treatment should target key checkpoints of pathogenesis, such as the depletion of reduced glutathione (GSH), which underlies the activation of the mechanistic target of rapamycin (mTOR) and inflammatory lineage specification of T cells, B-cell activation and antinuclear autoantibody production in SLE. The rationale for this study is supported by evidence that 1) GSH is depleted in peripheral blood lymphocytes (PBL) of SLE patients; 2) GSH depletion contributes to mTOR activation that drives T-cell dysfunction in SLE; 3) administration of N- acetylcysteine (NAC), which serves as a cell-permeable amino acid precursor of GSH, blocks the development of murine lupus; and 4) the preliminary studies suggest that NAC is safe, reverses GSH depletion and mTOR activation and improves disease activity in SLE patients. In our completed double-blind placebo-controlled pilot study, NAC was tolerated by 100% of patients on 1.2 g/day and 2.4 g/day dosages, while 33% of those receiving 4.8 g/day had reversible nausea. Placebo and 1.2 g/day NAC did not influence disease activity. Although both 2.4 g/day and 4.8 g/day NAC dosages showed preliminary evidence for clinical efficacy, 4.8 g/day NAC achieved greater drops in SLEDAI and BILAG scores. NAC raised GSH, blocked mTOR, and expanded T regs. The proposed phase II trial will employ the SLE Responder Index (SRI), as a clinically meaningful primary outcome measure that provides easily interpretable results and yields a feasible sample size that is associated with adequate power to detect therapeutic benefit over 1 year. To minimize potential intolerance of NAC and subject withdrawal, the study design includes an open-label dosage titration period. Patients who tolerate 2.4-4.8 g daily NAC for 3 months will be randomly assigned 1:1 to continue treatment on their tolerated dosage of NAC or matching placebo for 9 additional months. Beyond the premise of validating clinical efficacy and durability of this therapy in SLE, the proposed studies will test the hypothesis that depletion of GSH and cysteine and activation of mTOR predict immunobiological and clinical responsiveness to NAC. The proposed studies will significantly advance our understanding of immune-metabolic pathways that control T-cell lineage specification with translational relevance for the pathogenesis and treatment of lupus. The approach is innovative as it will employ a safe therapeutic intervention to define the role of cysteine depletion in redox-dependent mTOR activation and pro-inflammatory T-cell development in lupus patients in vivo. The results will bring new perspectives to our understanding of disease pathogenesis with broad translational relevance for clinical management of patients with SLE.

系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病，死亡率仍然很高 5年内接近10%。 SLE 死亡的主要原因是由毒性引起的感染 免疫抑制剂药物。因此，对有效且无毒的药物存在着巨大的未满足的需求 治疗 SLE 的药物。我们的中心假设是在有效治疗的基础上制定的 应针对发病机制的关键检查点，例如还原型谷胱甘肽 (GSH) 的消耗，这 是雷帕霉素机制靶点 (mTOR) 激活和炎症谱系规范的基础 SLE 中 T 细胞、B 细胞激活和抗核自身抗体产生的影响。这项研究的理由是 有以下证据支持：1) SLE 患者的外周血淋巴细胞 (PBL) 中 GSH 被耗尽； 2）谷胱甘肽 耗竭会导致 mTOR 激活，从而导致 SLE 中的 T 细胞功能障碍； 3) N-的施用 乙酰半胱氨酸 (NAC) 是 GSH 的细胞渗透性氨基酸前体，可阻止发育 鼠狼疮； 4) 初步研究表明 NAC 是安全的，可以逆转 GSH 消耗和 mTOR 激活并改善 SLE 患者的疾病活动性。在我们完成的双盲安慰剂对照试验中 研究显示，100% 的患者对 1.2 克/天和 2.4 克/天剂量的 NAC 具有耐受性，而其中 33% 的患者耐受 NAC 每天服用 4.8 克，出现可逆性恶心。安慰剂和 1.2 g/天 NAC 不影响疾病活动。 尽管 2.4 克/天和 4.8 克/天 NAC 剂量均显示出临床疗效的初步证据，4.8 克/天 NAC 在 SLEDAI 和 BILAG 分数上取得了更大的下降。 NAC 升高 GSH，阻断 mTOR，并且 扩展 T 寄存器。拟议的 II 期试验将采用 SLE 反应指数 (SRI) 作为临床指标 有意义的主要结果测量，可提供易于解释的结果并产生可行的样本 大小与检测一年内治疗效果的足够能力相关。最大限度地减少潜力 由于 NAC 不耐受和受试者停药，研究设计包括开放标签剂量滴定期。 每日耐受 2.4-4.8 g NAC 3 个月的患者将被随机分配 1:1 继续治疗 他们对 NAC 或匹配安慰剂的耐受剂量再持续 9 个月。超越验证的前提 该疗法在 SLE 中的临床疗效和持久性，拟议的研究将检验以下假设： GSH 和半胱氨酸的变化以及 mTOR 的激活可预测对 NAC 的免疫生物学和临床反应。 拟议的研究将显着增进我们对控制免疫代谢途径的理解 T 细胞谱系规范与狼疮发病机制和治疗的翻译相关性。这 该方法是创新的，因为它将采用安全的治疗干预来定义半胱氨酸耗竭的作用 狼疮患者体内氧化还原依赖性 mTOR 激活和促炎 T 细胞发育。这 结果将为我们理解具有广泛转化的疾病发病机制带来新的视角 与 SLE 患者临床管理的相关性。

项目成果

In Memoriam: Professor Joseph Biederman's Contributions to Child and Adolescent Psychiatry.

纪念约瑟夫·比德曼教授对儿童和青少年精神病学的贡献。

• 发表时间: 2024-03
• 作者: Faraone, Stephen V;Newcorn, Jeffrey H;Wozniak, Janet;Joshi, Gagan;Coffey, Barbara;Uchida, Mai;Wilens, Timothy;Surman, Craig;Spencer, Thomas J
• 通讯作者: Spencer, Thomas J

Attention-Deficit/Hyperactivity Disorder Is Associated With Increased Rates of Childhood Infectious Diseases: A Population-Based Case-Control Study.

注意力缺陷/多动症与儿童传染病发病率增加有关：一项基于人群的病例对照研究。

• 发表时间: 2023-02
• 影响因子: 13.3
• 作者: Merzon, Eugene;Israel, Ariel;Ashkenazi, Shai;Rotem, Ann;Schneider, Tzipporah;Faraone, Stephen V;Biederman, Joseph;Green, Ilan;Golan;Vinker, Shlomo;Weizman, Abraham;Manor, Iris
• 通讯作者: Manor, Iris

Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis.

ADHD 药物随机对照试验中的安慰剂和反安慰剂反应：系统评价和荟萃分析。

• 发表时间: 2022
• 影响因子: 11
• 作者: Faraone, Stephen V;Newcorn, Jeffrey H;Cipriani, Andrea;Brandeis, Daniel;Kaiser, Anna;Hohmann, Sarah;Haege, Alexander;Cortese, Samuele
• 通讯作者: Cortese, Samuele

Association Between ADHD and COVID-19 Infection and Clinical Outcomes: A Retrospective Cohort Study From Electronic Medical Records.

ADHD 和 COVID-19 感染与临床结果之间的关联：来自电子病历的回顾性队列研究。

• 发表时间: 2023-01
• 作者: Heslin, Kathleen P;Haruna, Aminat;George, Regina A;Chen, Shiyu;Nobel, Ishak;Anderson, Kathryn B;Faraone, Stephen V;Zhang
• 通讯作者: Zhang

Progress and Pitfalls in the Provision of Quality Care for Adults With Attention Deficit Hyperactivity Disorder in Primary Care.

初级保健中为注意力缺陷多动障碍成人提供优质护理的进展和陷阱。

• 发表时间: 2023-04
• 作者: Callen, Elisabeth F;Clay, Tarin L;Alai, Jillian;Goodman, David W;Adler, Lenard A;Shields, Joel;Faraone, Stephen V
• 通讯作者: Faraone, Stephen V