RAGE against diabetes complications: Novel drug tamps down tissue damage in mice

One of the many unfortunate effects of diabetes is that it causes excess inflammation in the body, which can lead to tissue damage and raise the risk of heart attacks and other adverse events. Researchers at New York University Grossman School of Medicine have developed a drug with a novel mechanism of action that they believe will prevent that harmful inflammation.

The drug, dubbed RAGE229, was designed to prevent a protein called rage from triggering inflammatory signals. In mouse models of diabetes, RAGE229 reduced the risk of heart attack and sped up the healing of diabetic wounds, the NYU team reported in Science Translational Medicine.

The high blood sugar that’s caused by both type 1 and type 2 diabetes has long been fingered as the culprit for inflammatory tissue damage. The NYU team studied the process by which high blood sugar creates that damage and discovered that the sugar kills cells, causing them to spill their contents.

Those contents include molecules that activate the rage protein, touching off a series of events that result in inflammation, the researchers explained in a statement. They screened a library of 59,000 drug compounds to find the one that best interfered with this process.

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The NYU team went on to test RAGE229 in mouse models of diabetes with temporary blockages of their coronary arteries. They found that 28% of heart muscle died in mice treated with the drug, vs. 38% in the control animals.

They then mixed RAGE229 into mouse chow to study the drug’s effect on long-term complications of diabetes, like wounds and kidney damage. They reported that 90% of mice treated with the drug saw their wounds close in 21 days, while just 65% of untreated mice healed. The treated mice also had “significantly less” kidney damage, according to the statement.

The development comes at a pivotal time in diabetes research. Last month, Vertex reported that its stem-cell-derived cell therapy candidate, VX-880, restored the function of insulin-producing islets in one patient in an ongoing clinical trial. The results were so compelling that RBC analysts declared the cell therapy to be a “game-changing off-the-shelf approach.”

Still, Vertex’s therapy is in a phase 1/2 trial, meaning it could take years to reach the market. So there’s still very much a need for new approaches to treating diabetes and its complications.

Among the research teams exploring new therapeutic targets for diabetes is one at the University of Utah, which reported last year that knocking out the T-cell-related protein OCA-B in mice protected them from diabetes. The University of Pittsburgh is working on a gene therapy for diabetes, as is startup Kriya, which recently raised $100 million to advance the treatment.

The next step for the NYU team is to modify and optimize RAGE229 to boost its potency. They hope to move an improved molecule into human trials soon, they said.