A new way to approach diabetes treatment

Mount Sinai researchers discover new drug cocktail that increases human beta cell proliferation at rapid rates

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NEW YORK—Like so many others worldwide, researchers in the Mount Sinai Health System would like to move beyond methods of controlling glucose levels and otherwise dealing with symptoms of diabetes, and instead attack the chronic disease by restoring the ability to actually produce insulin in diabetes sufferers.
Well, near the end of 2018, researchers at the Icahn School of Medicine at Mount Sinai made some progress on that front, announcing in a study titled “Combined Inhibition of DYRK1A, SMAD and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells” (published in Cell Metabolism) that they had discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells—the cells in the pancreas that produce insulin.
One of those types of drugs inhibits the enzyme known as dual specificity tyrosine-regulated kinase 1A (DYRK1A), and the other one inhibits members of the transforming growth factor beta superfamily (TGFβSF). According to the researchers, this drug combination caused beta cells to proliferate at a rate of 5 percent to 8 percent per day.
“We are very excited about this new observation because for the first time, we are able to see rates of human cell beta cell replication that are sufficient to replenish beta cell mass in human beings,” said Dr. Andrew Stewart, director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study. “We have discovered a drug combination that makes beta cells regenerate at rates that are suitable for treatment. The next big hurdle is figuring out how to deliver them directly to the pancreas.”
According to Stewart, none of the diabetes drugs currently on the market can induce beta cell regeneration in people with diabetes. As noted earlier, many researchers find that fact to be a problem, and in addition to the Mount Sinai's work, such researchers are studying options like pancreatic transplantation, beta cell transplantation and stem cell replacement of beta cells for people with diabetes. However, none of these approaches is in widespread use, Stewart points out, leaving exogenous insulin and other glucose-modulating drugs as the mainstays of diabetes treatment.
Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness and limb amputation. Loss of insulin-producing beta cells has long been recognized as a cause of type 1 diabetes, in which the immune system mistakenly attacks and destroys beta cells. In recent years, researchers have concluded that a deficiency of functioning beta cells is also an important contributor to type 2 diabetes, the most common type that occurs in adults. Thus, developing drugs that can increase the number of healthy beta cells is a major priority in diabetes research.
The recent Mount Sinai paper builds upon a study that Stewart and his team published in Nature Medicine in 2015, showing that a drug called harmine was able to drive sustained division and multiplication of adult human beta cells in culture. They also learned that harmine treatment led to normal control of blood sugar in mice whose beta cells had been replaced with human beta cells. While this was a major advance, the proliferation rate was lower than needed to rapidly expand beta cells in people with diabetes.
In 2017, Stewart and his team published a second paper, in Nature Communications, which revealed the genetic abnormalities in insulinomas, a benign type of human beta cell tumor, and served as a “genetic recipe” to reveal targets for new drugs that can make beta cells regenerate.
In this current paper, Stewart and his team took advantage of the insulinoma “genetic recipe,” which suggested that a combination of two classes of drugs—a DYRK1A inhibitor such as harmine with a TGFβSF inhibitor drug—would be able to synergistically increase beta cell regeneration. This proved to be true, the team says; however, this new drug combination is not without its hurdles.
“Since these drugs have effects on other organs in the body, we now need to develop methods to deliver these drugs specifically to the beta cell in humans,” reported Stewart. “We have the packages to deliver, but now we need a courier system to deliver them to the exact beta cell address.”
“Beta cell regeneration is a ‘holy grail’ for the treatment of diabetes,” said Dr. Peng Wang, an associate professor of medicine (endocrinology, diabetes, and blood disease) at Mount Sinai and first author on the study. “We are excited to finally have drugs that can induce beta cell proliferation at rates that are likely to be effective in people with type 1 and type 2 diabetes.”
“We know that in order to achieve a cure for type 1 diabetes and to bring people to insulin independence, we will have to find ways to increase the numbers of functional beta cells,” added Dr. Francis J. Martin, associate director of research and leader of the JDRF’s Beta Cell Regeneration and Survival Program. “Now, through the work of Drs. Stewart and Wang, we see that we can increase the rates of human beta cell reproduction to levels that were previously thought to be impossible. There are still challenges ahead, but this work brings us a little closer to therapies that can restore insulin production in people with the disease, and ultimately produce a cure.”
Speaking of the JDRF, about a day before Mount Sinai announced the publication of its paper, Pandion Therapeutics, a biotechnology platform company developing therapeutics to achieve localized immunomodulation to treat autoimmune and inflammatory disease, announced it had received an investment from the JDRF T1D Fund. This financing will enable the company to launch a type 1 diabetes (T1D)-focused program leveraging its innovative technology platform and pipeline. Pandion was founded in 2017 and closed a $58-million Series A financing round in early 2018 with funding from Polaris Partners, Versant Ventures, Roche Venture Fund, SR One and BioInnovation Capital. The investment from the JDRF T1D Fund will fund the evaluation of Pandion’s existing molecules for T1D, and in parallel, initiate the development of islet-specific tethers to pair with Pandion’s existing immunomodulators for T1D-specific drugs.

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