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:
- 金额:$ 27.97万
- 依托单位:
- 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:
- 关键词:AftercareAnimalsAnti-Inflammatory AgentsAntioxidantsArthritisAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityB-LymphocytesBindingBiological AssayBiological AvailabilityBiological MarkersBiological ProductsBone remodelingCartilageCellsChronicClinicalClinical TrialsCollagenCollagen ArthritisDiseaseDisease ProgressionDoseEGF geneEnzyme InhibitionEnzyme-Linked Immunosorbent AssayEnzymesExtracellular MatrixFemaleFinancial costFormulationGenerationsGenesGrantHourHumanHyperplasiaImmuneImmune responseImmunofluorescence ImmunologicImmunosuppressive AgentsImpairmentInfiltrationInflammationInflammation MediatorsInflammatoryInterleukin-6Interstitial CollagenaseIntraperitoneal InjectionsInvadedIsoprostanesJointsKneeKnee jointLeadLipidsMacrophageMalondialdehydeMatrix MetalloproteinasesMeasuresMediatingMedicalMinorityMusNitrogenOralOxidantsOxidative StressOxidoreductaseOxygenPainPathogenesisPathologyPatientsPharmaceutical PreparationsPhasePlasmaPolysaccharidesProductionProtein SProteinsProteoglycanQuality of lifeReactive Oxygen SpeciesResolutionReverse Transcriptase Polymerase Chain ReactionRheumatoid ArthritisRiskS-NitrosoglutathioneSafetySerum amyloid A proteinSeverity of illnessSignal PathwaySignal TransductionSignaling ProteinStainsSymptomsSystemT cell infiltrationTNF geneTNFSF11 geneTherapeuticTherapeutic InterventionTissuesToxic effectVEGFA geneVascular Cell Adhesion Molecule-1Workabsorptionarthropathiesbonechronic autoimmune diseasecytokinedisabilityefficacy evaluationimmune cell infiltrateimprovedin vivoinhibitorjoint destructionjoint inflammationlead candidatemalemitochondrial dysfunctionmouse modelnovelnovel therapeutic interventionoxidationoxidative damagepre-clinicalpreservationrestorationside effectsmall molecule inhibitortherapeutic 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-免疫反应周期。至关重要的是,先天的抗氧化系统
RA 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
炎症损伤。 SAJE Pharma [DBA:GSNO Therapeutics] 正在开发一种新型治疗方法
用于 RA 治疗,通过增加抗氧化和抗炎途径信号重建健康
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、
疾病产生蛋白质S-亚硝基化。 SAJE Pharma 的 GTI-891.1 抑制 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。 GSNOR
是 GSNO 的主要还原酶,GSNO 是人体最大的亚硝基化活性库;因此,它是一个有吸引力的
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。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。初步体内工作表明,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。该提案旨在
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。这笔赠款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,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。
项目成果
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