Investigational treatments of β-cell failure and replacement.

Overview

Diabetes is associated with β-cell destruction (Type 1) or functional failure (Type 2). Our research has shown that β-cell failure in Type 2 Diabetes is secondary to the progression of β-cell dedifferentiation. Until recently, it was unclear whether the process was reversible. By analyzing the molecular underpinning of β-cell dedifferentiation, we identified ectopic activation of the enzyme aldehyde dehydrogenase subtype 1A3 (ALDH1A3) as an early marker and effector of the process. Although the signaling pathways by which activation of ALDH1A3 impinges on β-cell function are still to be determined, the enzyme provides a tractable pharmacological target. We have shown that a proprietary, highly potent, and specific ALDH1A3 inhibitor can reverse β-cell dysfunction in animals. Clinical trials of a further version of this compound are being readied. Another area of our interest is the treatment of Type 1 Diabetes by conversion of intestinal epithelial cells into glucose-responsive insulin-producing, β-like cells. We have developed small molecule FoxO1 inhibitors that, when administered orally to diabetic rodents, can lower glycemia and generate insulin-immunoreactive intestinal cells. These cells can also be generated in NOD mice and lead to a restoration of insulin production, demonstrating that they are resistant to autoimmunity. Further preclinical studies are underway to test safety and efficacy of this approach as a Type 1 Diabetes treatment.