For more than 15 years, Ann Marie Schmidt, M.D., the Gerald and Janet Carrus Professor of Surgical Science, has been consumed with RAGE that is, the receptor for advanced glycation endproducts.
RAGE is a receptor Dr. Schmidt and her team discovered in the early 1990s while investigating why atherosclerosis develops early and with greater severity in people with diabetes.
This receptor’s acronym is catchy, but it also succinctly describes the effect of RAGE activity in diabetes. When active, the receptor ignites inflammatory and cellular processes that hasten the development of atherosclerosis and complications of diabetes that occur in small vessels as well.
Atherosclerosis is one of the most common and deadly complications faced by people with diabetes, and, therefore, experimental drugs that block RAGE have emerged as one of the most promising strategies to improve their lives. These drugs are currently in Phase II trials.
Unexpectedly, RAGE has also become a novel target for numerous other, seemingly unrelated, chronic diseases such as Alzheimer’s disease, cancer and immune system disorders.
“Cellular stress and inflammation responses are common threads underlying diverse chronic diseases. Although each disease may be triggered by something different, many appear to create a sustained state of cellular perturbation and inflammation that causes much of the damage,” Dr. Schmidt says. “RAGE provides not only an encompassing mechanism of chronic disease, but, of equal importance, a unique and highly targeted therapeutic strategy.”
A recent agreement with Pfizer will put that strategy to the test and accelerate the pace of clinical trials in chronic diseases in which RAGE appears to play a key amplifying role.
RAGE blockers created by TransTech Pharma, a small biotech company that teamed up with Dr. Schmidt in the late 1990s, have been licensed to Pfizer in the new agreement. TransTech has rights to all the RAGE technology discovered by Columbia scientists. Under the new agreement between TransTech and Pfizer, Pfizer gains exclusive rights to develop and commercialize the drug and related compounds produced by TransTech.
The key discovery that unfolded the biology of RAGE and its impact in a range of chronic disorders was that RAGE is activated by a discrete family of molecules. In diabetes, these molecules called AGEs (for advanced glycation endproducts) accumulate when glucose levels are not strictly controlled.
Originally, Dr. Schmidt thought that AGEs were the only molecules that activate RAGE. But additional research over the years has shown RAGE responds to several different kinds of inflammatory molecules that accumulate in chronic disease, including the amyloid-beta peptides and beta sheet fibrils in the brains of people with Alzheimer’s disease and S100s and amphoterins that are up-regulated in inflamed tissues.
Currently, Shi Du Yan, M.D., associate professor of clinical pathology, and colleagues, are probing the way RAGE activates stress pathways in neurons and microglia in the brains of Alzheimer’s patients.
Though it’s not entirely known what happens after RAGE is activated in Alzheimer’s and other chronic diseases, what is clear is that antagonizing RAGE suppresses injury-provoking pathways in animal models and can stop disease progression. For atherosclerosis in diabetic mice, drugs that target RAGE slow the formation of plaque to a rate seen in normal animals; in Alzheimer’s model mice, the drugs improve memory.
In humans, it’s still too early to know if the drugs have any effect, but so far, they appear to be safe in Phase I and Phase II trials.
For Dr. Schmidt, the start of trials and the Pfizer agreement are gratifying after nearly two decades of perseverance and hard work at the bench. “It took years of research to amass enough evidence before TransTech and then Pfizer would take a chance with RAGE,” Dr. Schmidt says. “Now, we look forward to seeing RAGE put to the ultimate test and we hope that in the hands of Pfizer and TransTech Pharma, our work may indelibly change the lives of people afflicted with chronic illness.”