RAGE229 is an experimental compound that has reduced complications of type 1 and type 2 diabetes in mice, not by lowering blood sugar, but by counteracting its consequences: cell death, inflammation and organ damage. To declare it is Ann Marie Schmidt, MD, Dr. Iven Young Professor of Endocrinology at NYU Grossman School of Medicine together with his research group.
The results of the study have been published in the scientific journal Science Translational Medicine.
RAGE229: this is what its function is
The study involving RAGE229 reported that A new class of compounds has blocked the ability of a protein called RAGE to transmit inflammatory signals that damage the heart and kidneys in diabetes and slow the healing of diabetic wounds.
The findings revolve around the body’s immune system, which recognizes and destroys invading bacteria and viruses. Activating this system causes inflammation, responses such as swelling and pain that result from the insertion of immune cells into sites of infection or injury. Many diseases, including diabetes, include out-of-place inflammation that damages tissues.
Experiments in human cells and mouse models found that the study’s lead compound, RAGE229, significantly reduced short- and long-term complications of diabetes.
“Our results establish the molecular backbone of RAGE229 as the basis for a novel approach that targets intracellular RAGE actions to counter diabetic tissue damage,” study lead author Ann Marie Schmidt said: “With further refinements, RAGE229 and its descendants have great potential to fill gaps in treatment, including the fact that most current medications only work against type 2 diabetes.
Most diabetes narratives state that diet and age (Type 2) or genetic differences (Type 1) reduce the action or production of the hormone insulin, which keeps blood sugar levels in check after that meals provide energy to the body.
While high blood sugar causes inflammatory damage, past work has also established that mechanisms that occur later and are common to both types of diabetes could be targeted separately by new drug candidates.
In particular, high blood sugar generates a greater number of charged particles that destroy cellular components such as DNA. This kills cells, which flake and shed their contents, including damage-associated molecular patterns or DAMPS. Such “hazard molecules” inform the body that a tissue is under stress, in some cases activating RAGE.
When a DAMP attaches to RAGE on the outer surface of a cell, it changes the shape of the receptor to transmit messages in the cell’s inner compartment, the cytoplasm. Schmidt and colleagues had previously shown that RAGE’s cytoplasmic “tail” (ctRAGE) interacts with a protein called DIAPH1 to transmit these messages, which ultimately activate inflammatory genes.
The current research team examined a library of 59,000 compounds to finally develop RAGE229, the candidate that interfered best with the DIAPH1: ctRAGE interaction.
Using a test that triggers inflammation in mice as measured by paw swelling, the team showed that those treated with RAGE229 had a significantly lower inflammation score of 2.5 (on a scale of 1 to 5) than a score. of 3.3 in mice given an inert solvent, also called a vehicle, useful for comparison.
Other experiments have shown the increased risk of heart attack in patients with diabetes, created in part by higher levels of inflammation. In male mice with type 1 diabetes and a temporary blockage of a coronary artery, simulating a heart attack, the researchers found that the amount of dead heart muscle (stroke volume) downstream of a blockage was 28%. in the mice treated with RAGE229, against 38% of mice treated with the inert solvent.
Subsequently The panel incorporated the RAGE229 molecule into mouse food because dietary intake could better measure its ability to reverse long-term complications such as diabetic wounds. High blood sugar and related inflammation have been shown to interfere with cells that create scar tissue to close wounds.
They found that the rate of wound closure after 21 days was 90 percent in the male type 2 diabetic mice treated with RAGE229, compared with 65 percent in those treated with the inert solvent. Both male and female mice treated with RAGE229 also had significantly better healing than mice treated with vehicle at the microscopic level (histological evidence).
The research team also found that male and female type 1 or type 2 diabetic mice fed RAGE229 Chow had significantly less kidney damage than mice fed RAGE229 Chow. Control chow based on various measures, including the reduction of mesangial sclerosis caused by inflammation – accumulation of proteins which reduces the ability of organs to adequately filter waste from the bloodstream.
“The RAGE229 used in our study will not be the recommended version should it transition to human clinical trials“, Concluded Schmidt:”We continue to synthesize and aggressively test new RAGE229 compounds and chemical modifications. These new molecules promise to provide a final drug candidate with optimal potency in the near future“.
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