Novel RAGE Antagonist Stirs Hopes for Countering Diabetic Complications

Diabetes complications manifest as elevated blood glucose levels and co-existing inflammation leading to tissue damage that raises the risk of heart attacks and other adverse events.

Despite the availability of a broad range of anti-diabetic agents, such as the glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase 4 (DPP4) inhibitors, they are known to cause therapeutic complications. 

Furthermore, these agents are largely recommended for patients with type 2 but not type 1 diabetes, which may limit any potential benefits for patients with type 1 diabetes. Hence, there remain important gaps in the therapeutic arsenal for diabetic complications.

However, researchers from New York University, NYU Langone Health, discovered a novel lead compound that assuaged short- and long-term complications of diabetes in mice without lowering blood glucose concentrations. Called “RAGE229”, the drug does this by countering the effects of circulating inflammatory molecules which cause tissue damage in vital organs.

Published recently in Science Translational Medicine, the study marks a treatment paradigm shift in diabetes and brings us closer to bridge the gaps in its existing therapeutic strategies.

Curbing RAGE to Ease Diabetes

In diabetic tissues, the receptor for advanced glycation end products (RAGE) bind AGEs and multiple pro-inflammatory ligands. Preclinical studies indicate that RAGE antagonists have beneficial effects on numerous complications of diabetes. 

However, these antagonists target the extracellular domains of RAGE, which bind distinct RAGE ligands at diverse sites in the immunoglobulin-like variable domain and two constant domains. The cytoplasmic tail of RAGE (ctRAGE) binds to the formin, Diaphanous-1 (DIAPH1), and this interaction is important for RAGE signaling.

Previously, the authors screened a library of >58,000 known small molecules and identified 13 small-molecule competitive inhibitors of ctRAGE interaction with DIAPH1; these molecules reduced RAGE ligand-mediated signaling and suppressed the acute inflammatory effects of RAGE ligands in vivo.

Addressing Inflammation, Ischemia and Chronic Conditions in Diabetes 

In the current study, the authors reported the discovery of RAGE229 as a ctRAGE-DIAPH1 inhibitor that blocked ctRAGE-DIAPH1 interaction and reduced the consequences of inflammation, ischemia, and long-term diabetes in mice with type 1- and/or type 2-like diabetes.

The NYU team demonstrated that the nondiabetic mice treated with RAGE299 and subjected to a delayed type hypersensitivity test using immunization followed by an inflammatory challenge showed significantly lower inflammation as compared to the mice treated with an inert solvent or a vehicle compound.

In addition, the authors showed the efficacy of RAGE229 in mitigating the risk for heart attack (myocardial infarction) in cardiac ischemia and diabetes mice model, created partly by increased inflammation in tissues. They showed that in male mice with type-1 like-diabetes, and a temporary blockage of a coronary artery, the volume of heart muscle tissue that died was significantly lower than the mice treated with a vehicle.

Next, the researchers investigated the efficacy of the compound to reverse long-term diabetes complications, such as wound healing. Elevated blood glucose levels and associated inflammation have been reported to interfere with wound healing. Interestingly, the researchers found out that topical administration of RAGE229 in type 2–like diabetic mice accelerated wound healing responses.

Further, they showed that in both male and female type 1– and type-2 like-diabetic mouse models of long-term diabetes–associated kidney disease, treatment with RAGE229 reduced multiple pathological and functional parameters relevant to diabetic kidney disease and set the stage for testing in humans.

Lastly, the authors also showed that diabetes increases plasma concentrations of inflammatory molecules in both type 1–like and type 2 murine diabetes models and that such elevations are significantly reduced by RAGE229 in both models.

Rationale for Targeting RAGE

Although there are certain limitations of the study, such as sex-dependent differences, dose-dependent effects of RAGE229 in some of the endpoints, including others; these present considerations notwithstanding, the plasma detectability, efficacy, and ability to affect multiple disease-relevant and inflammatory biomarkers of the diabetic state provide strong pharmacological proof of concept that small molecule antagonism of ctRAGE-DIAPH1 interaction,  may present a viable opportunity for the treatment of short-term and long-term complications of type 1–like and type 2–like diabetes.

Author

Isha Kapoor