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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要类风湿性关节炎 (RA) 是一种常见的自身免疫性关节疾病，涉及自身免疫、B 型和 T 型关节炎细胞浸润、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，进一步加剧炎症/氧化损伤-免疫反应循环。 RA 中受损；然而，蛋白质 S-亚硝基化的增加已被证明可以防止氧化剂和 SAJE Pharma [DBA：GSNO Therapeutics] 正在开发一种新的治疗方法。用于 RA 治疗，通过增加通过抑制 S-亚硝基谷胱甘肽还原酶 (GSNOR)，使相关蛋白质发生 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，导致异常、 SAJE Pharma 的 GTI-891.1 抑制疾病产生蛋白 GSNOR 增加 GSNO。水平并重建稳态蛋白 S-亚硝基化水平，无毒性或脱靶效应。是 GSNO 的主要还原酶，GSNO 是人体最大的亚硝基化活性库，因此它是一种有吸引力的酶；增加抗氧化和抗炎保护性 S-亚硝基化活性的治疗靶点 RA 中的信号传导，同时减少氧化和亚硝化损伤，而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进展，并且所有这些都带有严重副作用的风险。 GTI-891.1 具有出色的安全性，并且没有已知的抑制许多病理生理驱动因素的脱靶效应 RA 的初步体内研究表明，腹腔注射 GTI-891.1 可减少 RA 疾病。进展，改善临床评分，减少免疫细胞浸润和关节炎症，并减少 RA 胶原诱导关节炎 (CIA) 小鼠模型中的促炎细胞因子。扩展这些研究并通过口服给药评估 GTI-891.1 在 CIA 小鼠模型中的口服活性通过量化 GTI-891.1 治疗后疾病病理学的改善来评估其治疗潜力在 RA 实验性自身免疫 CIA 小鼠模型中，通过降低促炎细胞因子水平， T 细胞和炎症 B 细胞的浸润，SAJE 的 GTI-891.1 抑制 GSNOR 呈现出一种有前景的、 RA 管理和治疗的多方面方法。这项资助的工作将验证口服 GTI-891.1。介导的 GSNOR 抑制作为一种可行的治疗干预措施，可减轻 RA 进展并实现未满足的目标减少 RA 临床症状和改善患者生活质量的临床需求。