Diabetes affects 563 million people around the world. All common forms of diabetes result from inadequate numbers and function of pancreatic beta cells. This is the underlying rationale for attempts at beta cell replacement strategies including transplant of whole pancreas, isolated pancreatic islets, and/or stem cell-derived human beta-like cells. While tremendous progress has been made in each of these areas, it is unlikely that these approaches can be scaled to hundreds of millions, or even thousands, of people with diabetes.

Our approach has been to leverage fact that essentially all people with diabetes have some residual beta cells that could be subject to regenerative therapies. Through high-throughput drug screening and medicinal chemistry, we have identified and synthesized hundreds of small molecule inhibitors of the kinase DYRK1A. We have shown that DYRK1A inhibitors induce human beta cells to replicate, to expand dramatically in number when transplanted into immunodeficient mice, to enhance their function, to restore human insulin concentrations, and to reverse diabetes. Remarkably, this dramatic increase in human beta cell proliferation and mass is further enhanced by co-administration of widely used GLP1 receptor agonist (GLP1RA) drugs, exemplified by semaglutide.

Since DYRK1A is expressed in many tissues, one might expect that DYRK1A inhibitors might induce proliferation or other undesirable events in non-islet tissues. Reassuringly, during three months of treatment in human islet-bearing immunodeficient mice in which beta cell mass increased by 700%, no adverse events, effects or proliferation were observed in any tissue other than the beta cell. 

These safety and human efficacy findings have led to FDA approval of a Phase 1 dose-finding trial in human subjects. These reveal that beta cell-therapeutic concentrations of harmine can be readily achieved.

Collectively, these studies indicate that DYRK1A inhibitor therapy is: safe; remarkably effective in expanding human beta cell mass and function; is cost-effective; and, is scalable to millions of people with T1D and/or T2D, with or without addition of a GLP1RA. The safety and efficacy profile suggests that beta cell-specific drug targeting is unnecessary. Finally, through medicinal chemistry, novel DYRK1A inhibitors with greater potency and efficacy are in hand.