Researchers at Mount Sinai Health System in New York and City of Hope in Los Angeles have developed a therapy that promises to not only improve symptoms of diabetes but also has the potential to reverse the disease state through pancreatic beta-cell regeneration.
“This has been a 20-year effort among four labs and multiple highly talented researchers,” Andrew F. Stewart, MD, director of the Diabetes Obesity and Metabolism Institute at Mount Sinai told GEN.
The new study, titled, “Harmine and exendin-4 combination therapy safely expands human b cell mass in vivo in a mouse xenograft system,” was published in Science Translational Medicine.
Diabetes is a worldwide medical concern for more than 500 million people, nearly 10% of all adults. Current diabetes treatments address the symptoms of the disease, replacing insulin or increasing the body’s ability to utilize insulin. However, these treatments do not increase beta cell numbers, leaving a significant gap in reversing diabetes.
Stewart and his team in New York with California collaborators, including Adolfo Garcia-Ocaña, PhD, chair in gene regulation and drug discovery research at City of Hope, strategized that the best way to treat diabetes is to reverse the fundamental cause of the disease. “Beta cell deficiency underlies diabetes treatment strategies such as pancreas transplant, islet transplant, and new attempts at growing new beta cells from human stem cells,” remarked Stewart.
Together, they designed and implemented the first drug screens, followed by cell culture experiments, and as presented in the current study, animal transplant and drug treatment models.
The initial drug screening experiments identified a small molecule called harmine that can induce beta cell replication, which was published in 2015. This is a natural compound found in some plants that works by inhibiting the enzyme DYRK1A. Five years later, Stewart’s team showed that any of the GLP1 receptor agonists currently on the market synergize with any DYRK1A inhibitor to produce much higher rates of beta-cell replication.
The researchers’ earlier studies demonstrated that inhibiting DYRK1A in beta cells could induce short-term cell proliferation in vitro. They utilized an advanced laser microscopy technique called iDISCO+ to visualize and quantify beta-cell survival, function, and proliferation. iDISCO+ makes tissue transparent, allowing for 3D visualization of immunolabeled tissues.
Taken together, these data suggested that beta cells might grow in response to a combination treatment of harmine and GLP1. Further experimentation showed that the beta cells could survive in culture and the current study moved from tissue culture to studies in mice.
The researchers next took immunodeficient mice, typically used as models for diabetes research, with implanted human beta cells, and administered a combined treatment of harmine and GLP1. The results were profoundly positive, showing up to 700% increase in human beta cells over the three-month experimental duration. Stewart added, “In addition to beta cell mass expansion, diabetes reverses rapidly.”
“This is the first time that scientists have developed a drug treatment that is proven to increase adult human beta cell numbers in vivo,” said Garcia-Ocaña. “This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes.”
Stewart told GEN, “We had hoped that we would observe a small increase in human beta cell mass in vivo. But we never expected to see a 300–700% increase. This should be more than enough to ‘fill up the beta cell tank’ and reverse most types of human diabetes.”
Concurrent with this study, the Mount Sinai team has also completed a Phase I clinical trial of harmine to assess its safety and tolerability in healthy individuals. “We had hoped that we would observe no drug safety issues with drug treatment, and this is what we observed,” Stewart said of the trial.
Collaborators are also working on developing next-generation DYRK1A inhibitors as part of their continued research with the aim toward imminent clinical trials.
“Our studies pave the way for moving [other] DYRK1A inhibitors into human clinical trials and it’s very exciting to be close to seeing this novel treatment used in patients,” Garcia-Ocaña said. “There is nothing like this available to patients right now.”
Stewart concluded, “The steady progression from the most basic human beta cell biology, through robotic drug screening and now moving to human studies, illustrates the essential role for physician-scientists in academia and pharma.”
