Principal investigator Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine, right, and Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease).
About 420 million people in the world have Type 1 or Type 2 diabetes, including 30 million in the United States, and all suffer from reduced numbers of beta cells, says Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai. “There are 30 to 40 drugs on the market for diabetes, and none of them make beta cells regenerate,” he says. “Developing such a drug, and a precise way to deliver it, is our aim.”
A project led by Dr. Stewart recently received a $2.5 million, four-year grant from the National Institute of Diabetes Digestive and Kidney Disease, to support Mount Sinai researchers’ innovative efforts to regenerate insulin-producing beta cells that could lead to novel drugs for patients with diabetes.
Dr. Stewart’s team in 2015 identified the first potent human beta cell regenerative drug, harmine, which is in a class of drugs called DYRK1A inhibitors. They identified additional drugs that enhance the regenerative capabilities of harmine—TGF beta inhibitors in 2019, and GLP-1 receptor agonists in 2020. The new grant will support new efforts to develop a means to deliver these drugs precisely.
Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute, and Chalada Suebsuwong, PhD.
“These drugs clearly are effective but also have the potential to cause unwanted effects outside the beta cell, so we now need a way to target the beta cell regenerative drugs to the beta cell,” says Dr. Stewart, principal investigator of the grant. “In lay terms, we have a UPS package to make your beta cells better, but we do not yet know the address to deliver the package.” There are potential strategies for delivering these “packages” by attaching them to a GLP-1 receptor agonist or a monoclonal antibody, each a widely used type of drug.
The current project is a collaboration among Dr. Stewart; Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute; and Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.
The research has four aims: First, Dr. DeVita and his team are making TGF beta inhibitors that can be linked to other molecules targeting beta cells. Second, Dr. Moran is focused on making one such molecule, a monoclonal antibody, which can deliver the drugs to beta cells. Third, Dr. Stewart and Dr. DeVita will “conjugate” the drugs with the delivery methods to investigate which combinations work the best. And fourth, Dr. García-Ocaña will test the therapies on human beta cells in mice.
Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.
“We are excited about these collaborative and translational studies that link basic laboratory research with ultimate goal of treating patients. For the first time, we have a series of new molecules that could be effective for both major forms of diabetes,” Dr. DeVita says. “If successful, a new targeted molecule could be scaled up in the future for further drug development, with the potential to treat millions of people around the world.”
Dr. Stewart is the site principal investigator for another grant for the study of diabetes, obesity, and other metabolic disorders, which was recently renewed by the National Institutes of Health. That five-year, $9.5 million grant was awarded to support the Einstein-Mount Sinai Diabetes Research Center, a regional collaborative led by Jeffrey Pessin, PhD, the Judy R. and Alfred A. Rosenberg Professorial Chair in Diabetes Research at the Albert Einstein College of Medicine and principal investigator on the grant.
The Center was founded in 1976 and has long focused its efforts on minority and other underserved populations in the region. Five years ago, it expanded into a regional collaborative, partnering with Mount Sinai to increase its capacity to support research studies and services. “The idea of these center grants is to have a series of cores that allow us to help people who are doing research, to do it faster, better, and more cost-efficiently,” Dr. Stewart says. For example, at Mount Sinai a core providing expertise in immune technology is led by Dirk Homann, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); and a human islet adenovirus core is led by Dr. García-Ocaña.
“The Center has provided a major boost to basic science and clinical diabetes and obesity research and training efforts at both Mount Sinai, Albert Einstein College of Medicine, and multiple other medical schools in the greater New York region,” Dr. Stewart says. “The Einstein team has been an extraordinary scientific partner.”