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.
Public Health Relevance Statement: PROJECT NARRATIVE SAJE Pharma [DBA: GSNO Therapeutics] is developing GTI-891.1 a small molecule inhibitor of GSNOR which is a denitrosylation enzyme that regulates S-nitrosylation protein signaling, as a potent, multifaceted therapeutic approach to mitigate inflammation, oxidative stress, mitochondrial dysfunction, and immune cell invasion in rheumatoid arthritis. This project will validate the use of oral GTI-891.1 to reduce clinical signs of disease in the experimental collagen induced rheumatoid arthritis mouse model.
Project Terms: absorption; After Care; After-Treatment; post treatment; Aftercare; Amyloid A Precursor; Amyloid A Protein-Related Serum Component; Amyloid Protein AA Precursor; Amyloid Protein SAA; Amyloid Serum Protein SAA; Amyloid-Related Serum Protein (SAA); Serum A Related Protein; Serum Amyloid A; Serum amyloid A protein; Animals; inhibitor; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Antioxidants; anti-oxidant; Arthritis; arthritic; Rheumatoid Arthritis; Atrophic Arthritis; rheumatic arthritis; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Autoimmune Diseases; autoimmune condition; autoimmune disorder; autoimmunity disease; Autoimmune Responses; Autoimmunity; Autoimmune Status; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; bone; Cartilage; Cartilaginous Tissue; Cells; Cell Body; Clinical Trials; Collagen; Financial cost; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Enzymes; Enzyme Gene; Extracellular Matrix; Cell-Extracellular Matrix; ECM; Female; Genes; Grant; Human; Modern Man; Hyperplasia; Hyperplastic; Immunosuppressive Agents; Immunosuppressants; Immunosuppressive drug; Immunosuppressive treatment; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; Inflammation; Intraperitoneal Injections; IP injection; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; arthropathies; Joint Diseases; arthropathic; arthropathy; joint disorder; Joints; Knee; Knee joint; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipids; Macrophage; MÏ; male; Malondialdehyde; Malonaldehyde; Malonylaldehyde; Malonyldialdehyde; Propanedial; Mus; Mice; Mice Mammals; Murine; Nitrogen; oxidation; Oxidoreductase; Dehydrogenases; Oxidoreductase Gene; Reductases; Oxygen; O element; O2 element; Pain; Painful; Pathology; Patients; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Polysaccharides; Glycans; Production; Proteins; Proteoglycan; Quality of life; QOL; Risk; Safety; Signal Pathway; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Stains; Staining method; Tissues; Body Tissues; Work; Protein S; Cofactor Protein S; Vitamin K-Dependent Protein S; S-Nitrosoglutathione; S-Nitroso-GSH; Vascular Cell Adhesion Molecule-1; CD106; CD106 Antigens; INCAM-110; Inducible Cell Adhesion Molecule 110; VCAM; VCAM-1; Vascular Cell Adhesion Molecule; cytokine; Generations; Immunofluorescence Immunologic; Immunofluorescence; Measures; bone remodelling; Bone remodeling; Oxidizing Agents; electron acceptor; Oxidants; Mediating; MMP-1; MMP-1Fibroblast Collagenase; MMP1; Matrix Metalloproteinase-1; Interstitial Collagenase; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Reactive Oxygen Species; improved; Chronic; Clinical; Phase; Medical; disability; Oxidative Stress; Disease Progression; inflammatory mediator; Inflammation Mediators; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Infiltration; Inflammatory; Hour; Immune; Immunes; Oral; System; restoration; Severity of illness; disease severity; joint destruction; joint degeneration; joint degradation; joint tissue degeneration; Reverse Transcriptase Polymerase Chain Reaction; RT-PCR; RTPCR; reverse transcriptase PCR; Toxic effect; Toxicities; Matrix Metalloproteinases; MMPs; novel; Pathogenesis; Therapeutic Intervention; intervention therapy; TNF gene; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Isoprostanes; Collagen-Induced Arthritis; Collagen Arthritis; Molecular Interaction; Binding; Signaling Protein; Signaling Factor Proto-Oncogene; Signaling Pathway Gene; VEGFA gene; VEGFA; Vascular Endothelial Growth Factor A; Vasculotropin; TNFSF11 gene; OPGL; RANKL; TNFSF11; hRANKL2; sOdf; EGF gene; EGF; Dose; Symptoms; Resolution; resolutions; in vivo; Invaded; Enzyme Inhibition; pre-clinical; preclinical; chronic autoimmune disease; Minority; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Impairment; mitochondrial dysfunction; murine model; mouse model; therapeutic target; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; bio-markers; biologic marker; biomarker; Biological Markers; oxidative injury; oxidative damage; Formulation; small molecule inhibitor; preservation; lead candidate; inflamed joint; joint swelling; joint inflammation; side effect; Autoimmune; T cell infiltration; immune cell infiltrate; Immune infiltrates
