Periodic Reporting for period 3 - Reprogram-Diabetes (In vivo drug discovery for cellular reprogramming to β-cells – towards a future regenerative therapy for diabetes) Reporting period: 2021-07-01 to 2022-12-31 Summary of the context and overall objectives of the project For almost a century we have been able to control diabetes with insulin injections, yet we still have no cure for this prevalent disease. Despite their mechanistic differences, both type 1 and the late stages of type 2 diabetes feature a reduction of functional β-cells, a key pathologic event that causes or exacerbates the dysregulation of glucose levels. One possible way to cure diabetes is by increasing the number of insulin producing beta-cells in the pancreas. In this project, we are addressing this issue by screening for drug candidates that may help regenerate the beta-cell population. Our overarching goal is to identify clinically viable extracellular factors that can induce cellular reprogramming to beta-cells and thereby increase the beta-cell mass and improve glucose control in diabetes. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far We have screened libraries containing around 5000 small molecules while monitoring cellular reprogramming to beta-cells, i.e. with an origin from three different pancreatic cell types. We have identified 4 small molecules that we are currently investigating in detail. In a second line of research we are testing genetic candidates that can induce cellular reprogramming to beta-cells. We have identified and tested around 20 genes and found that one can induce regeneration of beta-cells, and we are currently characterizing the cellular origin leading to an increased number of beta-cells. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) We have succeeded to perform the largest in vivo small molecule screen for cellular reprogramming in any species, and any cell type, to date.