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

项目总结 类风湿关节炎(RA)是一种流行的关节自身免疫性疾病，涉及自身免疫、B和T 细胞渗透、线粒体功能障碍、细胞外基质降解、氧化应激和炎症，最终 导致软骨破坏和骨骼重吸收。氧化应激是类风湿性关节炎的一个标志：活性氧 (ROS)通过蛋白质、脂类和多糖的氧化造成直接损害，包括软骨的氧化 蛋白多糖，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。最重要的是，天生的抗氧化系统 在RA中是受损的；然而，S亚硝化蛋白的增加已被证明可保护其免受氧化剂和 炎性损伤。SAJE Pharma[DBA：GSNO Treeutics]正在开发一种新的治疗方法 对于类风湿关节炎的治疗，通过增加 蛋白质S亚硝化对相关蛋白质的抑制作用是通过抑制酶S亚硝基谷胱甘肽还原酶(GSNOR)实现的。 GSNOR活性在许多炎症和氧化应激相关疾病中升高，导致异常， 疾病产生蛋白S-亚硝化。SAJE Pharma的GTI-891.1抑制GSNOR增加GSNO 并重新建立动态平衡蛋白S-亚硝化水平，无毒性或脱靶效应。GSNOR 是GSNO的主要还原酶，GSNO是人体最大的亚硝化活性储存库；因此，它是一个有吸引力的 提高保护性S-亚硝基抗氧化抗炎活性的治疗靶点 在RA中传递信号，同时减少氧化和亚硝化损伤。虽然现有的治疗方法有助于管理患者 疼痛和症状，只有少数人可以减缓疾病的进展，并且都有严重副作用的风险。 Gti-891.1具有极好的安全性，并且没有已知的非靶点效应抑制许多病理生理驱动因素 在RA中。初步的体内研究表明，GTI-891.1通过腹腔注射可以减少RA疾病的发生 进展，改善临床评分，减少免疫细胞渗透和关节炎症，并减少 类风湿性关节炎(CIA)小鼠模型中的促炎细胞因子。这项建议旨在 扩大这些研究，并通过口服剂量评估GTI-891.1‘S在CIA小鼠模型RA中的口服活性 通过量化GTI-891.1治疗后疾病病理改善来评估其治疗潜力 在实验性自身免疫性RA的CIA小鼠模型中。通过降低促炎细胞因子水平， T细胞和炎性B细胞的渗透，SAJE的GTI-891.1抑制GSNOR是一种有希望的治疗方法， 多面化的类风湿关节炎管理和治疗方法。这项资助中的工作将验证口头GTI-891.1 介导的GSNOR抑制作为一种可行的治疗干预措施来减缓类风湿关节炎的进展并实现未满足的 临床需要减少类风湿关节炎的临床症状，提高患者的生活质量。

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.