Modulation of Protein S-nitrosylation Signaling as a Potential Therapeutic Breakthrough in Rheumatoid Arthritis

调节蛋白质 S-亚硝基化信号传导是类风湿关节炎的潜在治疗突破

• 批准号: 10817318
• 负责人: Matthews Ogden Bradley
• 金额: $ 27.97万
• 依托单位: GSNO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10817318
• 关键词: Aftercare; Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; Biological Availability; Biological Markers; Biological Products; Bone remodeling; Cartilage; Cells; Chronic; Clinical; Clinical Trials; Collagen; Collagen Arthritis; Disease; Disease Progression; Dose; EGF gene; Enzyme Inhibition; Enzyme-Linked Immunosorbent Assay; Enzymes; Extracellular Matrix; Female; Financial cost; Formulation; Generations; Genes; Grant; Hour; Human; Hyperplasia; Immune; Immune response; Immunofluorescence Immunologic; Immunosuppressive Agents; Impairment; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Interstitial Collagenase; Intraperitoneal Injections; Invaded; Isoprostanes; Joints; Knee; Knee joint; Lead; Lipids; Macrophage; Malondialdehyde; Matrix Metalloproteinases; Measures; Mediating; Medical; Minority; Mus; Nitrogen; Oral; Oxidants; Oxidative Stress; Oxidoreductase; Oxygen; Pain; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase; Plasma; Polysaccharides; Production; Protein S; Proteins; Proteoglycan; Quality of life; Reactive Oxygen Species; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Risk; S-Nitrosoglutathione; Safety; Serum amyloid A protein; Severity of illness; Signal Pathway; Signal Transduction; Signaling Protein; Stains; Symptoms; System; T cell infiltration; TNF gene; TNFSF11 gene; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; VEGFA gene; Vascular Cell Adhesion Molecule-1; Work; absorption; arthropathies; bone; chronic autoimmune disease; cytokine; disability; efficacy evaluation; immune cell infiltrate; improved; in vivo; inhibitor; joint destruction; joint inflammation; lead candidate; male; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; oxidation; oxidative damage; pre-clinical; preservation; restoration; side effect; small molecule inhibitor; therapeutic target

PROJECT SUMMARY Rheumatoid arthritis (RA) is a prevalent autoimmune disease of the joints that involves autoimmunity, B and T cell infiltration, mitochondrial dysfunction, ECM degradation, oxidative stress and inflammation, that ultimately lead to cartilage destruction and bone reabsorption. Oxidative stress is a hallmark of RA: reactive oxygen species (ROS) inflict direct damage via the oxidation of proteins, lipids, and glycans, including oxidation of cartilage proteoglycans, and act as secondary messengers to activate regulators of inflammatory genes, further exacerbating the inflammation/oxidative damage-immune response cycle. Critically, innate anti-oxidant systems are impaired in RA; however, increases in protein S-nitrosylation have been shown to protect from oxidant and inflammatory damage. SAJE Pharma [DBA: GSNO Therapeutics] is developing a novel therapeutic approach for RA treatment that reestablishes healthy antioxidative and anti-inflammatory pathway signaling by increasing protein S-nitrosylation on relevant proteins by inhibiting the enzyme S-nitrosoglutathione reductase (GSNOR). GSNOR activity is elevated in many inflammatory and oxidative stress related diseases resulting in abnormal, disease producing protein S-nitrosylation. GSNOR inhibition by SAJE Pharma's GTI-891.1 increases GSNO levels and reestablishes homeostatic protein S-nitrosylation levels, without toxicity or off-target effects. GSNOR is the major reductase of GSNO, the body's largest reservoir of nitrosylating activity; therefore, it is an attractive therapeutic target for increasing protective S-nitrosylating activity for antioxidative and anti-inflammatory signaling in RA, while reducing oxidative and nitrosative damage. While existing therapies help manage patient pain and symptoms, only a minority can slow disease progression, and all carry risks for serious side effects. GTI-891.1 has excellent safety profiles and no known off-target effects inhibiting many pathophysiological drivers of RA. Preliminary in vivo work demonstrates that GTI-891.1 by intraperitoneal injection reduces RA disease progression, improves clinical scores, reduces immune cell infiltration and inflammation in joints, and reduces pro-inflammatory cytokines in the collagen-induced arthritis (CIA) mouse model of RA. This proposal aims to extend those studies and evaluate GTI-891.1’s oral activity in the CIA mouse model of RA via oral dosing to assess its therapeutic potential by quantifying disease pathology improvements after treatment with GTI-891.1 in an experimental autoimmune CIA mouse model of RA. By reducing pro-inflammatory cytokine levels, infiltration of T and inflammatory B cells, GSNOR inhibition by SAJE's GTI-891.1 presents a promising, multifaced approach for RA management and treatment. The work in this grant will validate oral GTI-891.1 mediated GSNOR inhibition as a viable therapeutic intervention to mitigate RA progression and fulfill an unmet clinical need for reducing clinical signs of RA and improving patient quality of life.

项目摘要 类风湿性关节炎（Rheumatoid arthritis，RA）是一种常见的自身免疫性关节疾病，涉及自身免疫、B和T 细胞浸润，线粒体功能障碍，ECM降解，氧化应激和炎症，最终 导致软骨破坏和骨重吸收。氧化应激是RA的标志：活性氧 (ROS)通过蛋白质、脂质和聚糖的氧化（包括软骨的氧化）造成直接损伤 蛋白聚糖，并作为第二信使激活炎症基因的调节因子， 加剧炎症/氧化损伤-免疫应答循环。关键是，先天抗氧化系统 在RA中受损;然而，蛋白质S-亚硝基化的增加已被证明可以保护免受氧化剂的影响， 炎性损伤SAJE Pharma [DBA：GSNO Therapeutics]正在开发一种新的治疗方法 对于RA治疗，通过增加抗氧化和抗炎途径信号传导， 通过抑制酶S-亚硝基谷胱甘肽还原酶（GSNOR），对相关蛋白质进行蛋白质S-亚硝基化。 GSNOR活性在许多炎症和氧化应激相关疾病中升高， 致病蛋白S-亚硝基化。SAJE Pharma的GTI-891.1的GSNOR抑制增加了GSNO 水平和重建稳态蛋白S-亚硝基化水平，没有毒性或脱靶效应。GSNOR 是GSNO的主要还原酶，GSNO是体内最大的亚硝基化活性库;因此，它是一种有吸引力的 用于增加抗氧化和抗炎的保护性S-亚硝基化活性的治疗靶点 信号，同时减少氧化和亚硝化损伤。虽然现有疗法有助于管理患者 疼痛和症状，只有少数可以减缓疾病的进展，所有的风险，严重的副作用。 GTI-891.1具有良好的安全性，并且没有已知的脱靶效应，可抑制许多病理生理驱动因素 的RA。初步的体内研究表明，腹膜内注射GTI-891.1可减少RA疾病 进展，改善临床评分，减少关节中的免疫细胞浸润和炎症， 促炎细胞因子在RA的胶原诱导的关节炎（CIA）小鼠模型中。这项建议旨在 扩展这些研究，并通过口服给药评价GTI-891.1在RA CIA小鼠模型中的口服活性， 通过量化GTI-891.1治疗后的疾病病理学改善来评估其治疗潜力。 在RA的实验性自身免疫性CIA小鼠模型中。通过降低促炎细胞因子水平， T和炎性B细胞的浸润，SAJE的GTI-891.1对GSNOR的抑制呈现出有希望的， RA管理和治疗的多方面方法。这项资助的工作将验证口头GTI-891。 介导的GSNOR抑制作为一种可行的治疗干预措施，以缓解RA进展并实现未满足的 减少RA临床体征和改善患者生活质量的临床需求。