Genetic inactivation of the nuclear transcription factor Forkhead box protein O1 (FOXO1) in mice in specific intestinal endocrine progenitor cells reprograms them into glucose-responsive insulin- producing (beta-like) cells, raising the promise that the gut can serve as an endogenous source for beta cell replacement. This phenomenon has also been demonstrated in vitro in cells derived from small and large intestinal tissues of normal human subjects and treated with FOXO1 inhibitors. Recent work in Dr. Accili’s lab identified a novel population of FOXO1-expressing cells in the glandular epithelium of the stomach in mice, which can be converted to beta-like cells upon FOXO1 genetic ablation. Whether the human stomach also harbors a FOXO1+ cell population that can be converted to beta-like cells is unknown. Furthermore, since type 1 diabetes (T1D) has been linked to gut epithelial dysfunction, questions remain as to whether the distribution of gut FOXO1+ cells in T1D resembles that in non-diabetics and whether the capability for these cells to convert into beta-like cells upon FOXO1 inhibition is preserved in T1D. Finally, whether the converted beta-like cells can survive ongoing autoimmunity in the T1D setting remains unknown.

The objectives of the proposed addendum is to leverage the expertise in Dr. Accili’s lab at Columbia University to characterize FOXO1 distribution in non-diabetic and T1D stomach tissues, use an in vitro system to determine the ability of FOXO1 inhibitors to convert cells in primary stomach cultures to beta-like cells, and examine the viability of the converted beta-like cells in an in vitro model of autoimmunity using autologous cytotoxic immune cells. The proposed work is expected to generate key in vitro proof-of-concept data to validate the stomach (in addition to the intestine) as a source of beta-like cell conversion by FOXO1 inhibitors and to inform an ongoing drug discovery program regarding the optimal absorption and distribution profiles for FOXO1 inhibitors as novel therapeutics for T1D.