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Novel Approach Uses mRNA for MafA Transfer Factor to Reprogram Pancreatic Duct-Derived Cells to Produce and Secrete Insulin in Response to Glucose; May Speed Development of Transplantable Cells to Treat Diabetes

A new technique to produce cells with insulin-secretion capabilities has been developed, according to research presented at the 54th Annual European Society for Paediatric Endocrinology Meeting in Barcelona, Spain (October 1-3, 2015). The technique could be further developed to be used in the transplantation for patients with type 1 diabetes. It is well established that, typically, in type 1 diabetes, the body's immune system mistakenly attacks and destroys beta cells in the pancreas. These unique cells are responsible for producing, storing, and secreting insulin - the hormone that regulates levels of glucose in the blood. Currently one of the most promising therapies in the fight against diabetes is the replacement of beta cells. In the replacement therapy for type 1 diabetes, researchers from Université Catholique de Louvain in Belgium have previously shown that human pancreatic duct-derived cells (HDDCs) are an attractive source of cells that may potentially be reprogrammed to behave like beta cells. The HDDCs are found in the adult pancreas and are progenitor cells - cells that have a tendency and the capacity to differentiate into specific types of other cells. In this study, the research group reprogrammed HDDCs to behave like beta cells and secrete insulin within the pancreas, whilst responding to glucose. The researchers used messenger RNA (mRNA) for a specific transcription factor - a protein that controls which genes are turned off or on in the genome - called MafA (image). The mRNA codes for the production of the MafA protein that binds to nuclear DNA in order to orchestrate the changes in cellular functions. This technique allowed the researchers to avoid any potential genetic modification of the target cells.

"The novelty of our work resides in the use of adult tissue that avoids the risks related to stem cells, such as cancer, and of a protocol that modifies the cells with a direct action on DNA without any structural modification," said lead investigator Professor Philippe Lysy.

"Our system for cellular reprogramming with transcription factors using mRNA opens doors for experiments in other scientific fields with the objective to produce cells with a new function in the context of diseases with a loss-of-function."

The group has already developed a mouse model that allows them to transplant their manufactured cells into the diabetic mice and follow-up on their disease.

At the same time, the group uses a “good laboratory practice (GLP)” facility to produce batches of cells that could eventually be transplanted into human patients with diabetes.

"With ongoing in vivo studies, we are analyzing the potential of our reprogrammed cells to function and secrete insulin into a body according to blood glucose levels," Professor Lysy said.

"Our objectives are to evaluate the conditions that allow banking of our reprogrammed cells in clinically compatible procedures," he said.

[Press release] [54th Annual European Society for Paediatric Endocrinology Meeting (2015)]