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

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.