Making Human Beta Cells by Reprogramming Exocrine Pancreas (FWOAL844)

Patients with diabetes have insufficient numbers of insulin-producing beta cells in the pancreas. Human beta cells are notoriously difficult to generate and therefore multiple pathways to beta cell regeneration need to be explored. The presently proposed approach to regenerative therapy is based on reprogramming cells from adult human exocrine pancreas towards beta(-like) cells by ectopic expression of a selected set of developmental transcription factors. Although we already provided proof of concept for the current version of this strategy, its efficiency is suboptimal and its clinical applicability is low. We therefore plan to first test the reproducibility of the reprogramming protocol, adding extra quality controls of the source cells and deep characterization of the target cells. Secondly, safety and efficiency will be optimized by (i) use of synthetic mRNAs encoding the transcription factors, (ii) modifying the smRNAs for increased stability and lowered immunogenicity, (iii) improving smRNA delivery, (iv) use of clonally expanded exocrine cells and (v) use of specific epigenetic modifiers. Finally, we will re-evaluate the minimal transcription factor complement for reprogramming using a novel network-based computational framework. Ultimately we aim to establish a method that supports cell therapy for diabetes patients by transplantation of in vitro-generated beta(-like) cells.

Keywords:HUMAN BETA CELLS, DIABETES

Disciplines:Anatomical pathology