Could gene therapy one day cure type 1 diabetes?

For years, scientists have been interested in whether alpha cells might be able to be reprogrammed to do the work of insulin-producing beta cells in type 1 diabetes.

A new study published in the journal Cell Stem Cell demonstrates an early look how one day gene therapy might be used to permanently restore normal blood glucose levels in people with type 1 diabetes.

The work, which reprogrammed the glucagon-producing alpha cells to produce insulin, restored normal blood glucose levels in the diabetic mice for about four months.

Using what’s known as an adeno-associated virus, researchers at the University of Pittsburgh School of Medicine and the Children’s Hospital of Pittsburgh delivered two proteins, Pdx1 and MafA, to the mouse pancreas that could reprogram alpha cells into beta cells.

In people, this could be done endoscopically, delivering a protein-containing liquid to the pancreas via a tube that connects it to the intestine.

In the diabetic mice, it required surgery. At least initially, it worked. The alpha cells began producing insulin and restored normal blood glucose levels in the diabetic mice for about four months.

Though the concept has so far only been tested in mice, it demonstrates what could be an important new area of exploration in searching for a diabetes cure.

Alan Attie, whose University of Wisconsin lab studies the genetic and biochemical processes underlying genetics, called it «beautiful and elegant work.»

But it raised some questions that scientists are still to answer: Why didn’t the mouse immune system immediately attack the engineered beta cells? What is the effect of transforming pancreatic alpha cells in the long term? And of course, how would all this work in people?

Eric Topol, a Scripps Research Institute geneticist, said that while the work was «interesting and creative» the fact that after four months the immune system started attacking those beta cells suggested that this is unlikely to be a one-time cure, and raises questions of how long those four months would translate to in humans.

Study summary

Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin+ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

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