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

Project Information

Reprogram-Diabetes

Grant agreement ID: 772365

DOI

10.3030/772365

Project closed

EC signature date 14 March 2018

Start date 1 July 2018

End date 30 September 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 968,00

EU contribution

€ 1 999 968,00

Coordinated by

UPPSALA UNIVERSITET
Sweden

Periodic Reporting for period 5 - Reprogram-Diabetes (In vivo drug discovery for cellular reprogramming to β-cells – towards a future regenerative therapy for diabetes)

Reporting period: 2024-03-01 to 2024-09-30

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 four different pancreatic cell types. We have identified a handful small molecules that we have investigating in detail. In a second line of research, we have tested genetic candidates that can induce cellular reprogramming to beta-cells. We have tested around 30 genes and identified a couple that can induce regeneration of beta-cells, as well as characterized the cellular origin leading to an increased number of beta-cells.
For most of the studies in this project we translated the findings from zebrafish to mouse, pig, or human cells. Moreover, we have delineated the mechanisms underlying the increase in beta-cells using transcriptomics, such that all of our findings were finalized as mechanistic studies giving a deeper understanding of the induced effects.
We have published articles with these findings as well as presented the research at conferences, and believe that other scientists will make use of these results in further translation and exploitation for future management of diabetes.

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 stimulating cellular reprogramming, as well as identified small molecules stimulating differentiation of ductal cells to insulin-producing beta-cells. The hits include several small molecules, including folate and inhibitors of the protein MNK2, stimulating ductal cell differentiation to beta-cells, as well as Adjudin stimulating beta-cell maturation and functioning.
Moreover, we developed a versatile method for knocking in DNA into specific regions of the genome, thereby making novel zebrafish lines that can be used for lineage tracing cellular origins. This novel method for generating zebrafish knock-in lines was a thought through development that made it straightforward to generate plentiful of knock-in zebrafish lines, enabling ourselves and others to scale up this process. Combining the lineage tracing with single cell transcriptomics we decoded the differentiation trajectory of post-embryonic beta-cells and found that inhibitors of the PI3K signaling pathway could stimulate this process.
The results we gained in this ERC consolidator project are at the forefront of science using zebrafish, and serve both as an entry point to studying regeneration and biological mechanisms as well as can provide future drug candidates. Thus, we envision that our findings will eventually have implication for human disease.

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