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In vivo drug discovery for cellular reprogramming to β-cells – towards a future regenerative therapy for diabetes

Periodic Reporting for period 2 - Reprogram-Diabetes (In vivo drug discovery for cellular reprogramming to β-cells – towards a future regenerative therapy for diabetes)

Reporting period: 2020-01-01 to 2021-06-30

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.
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.
We have succeeded to perform the largest in vivo small molecule screen for cellular reprogramming in any species, and any cell type, to date.