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Turning pancreatic alpha cells into insulin-producing beta-like cells via gene therapy

Scientists have developed a new way to replace lost beta cells in mouse models of type 1 diabetes.  Type 1 diabetes stems from a misguided autoimmune attack destroying the pancreas’ insulin-producing beta cells, which reside in cell clusters called islets.  Insulin therapy is a life-saving treatment for this disease, but it is difficult to keep blood glucose (sugar) levels within the recommended range with current therapies.  Scientists are studying new ways to replace lost beta cells, and one approach is to “reprogram” other pancreatic cells—such as glucagon-producing alpha cells, which are also in the islets—to take over beta cells’ function.  Toward this end, one group of scientists has used a repurposed virus as a vehicle to deliver extra copies of two genes involved in beta cell maturation and function (Pdx1 and Mafa) into the mouse pancreas.  They gave this gene therapy to mice who had diabetes because their beta cells had been destroyed. After the therapy, the mice no longer had diabetes, and their blood glucose levels stayed in the normal range until the experiment’s end 6 months later.  Researchers found that the Pdx1 and Mafa genes were delivered to pancreatic alpha cells, where the genes prompted the alpha cells to become beta cell-like and produce insulin.

However, could this approach effectively treat diabetes in a mouse model mimicking the ongoing autoimmune attack seen in people with type 1 diabetes, or would this autoimmune response destroy the newly reprogrammed insulin-producing cells?  To answer these questions, the researchers gave the Pdx1 and Mafa gene therapy to mice made diabetic due to an ongoing autoimmune attack that destroyed their beta cells.  Mice that received the therapy soon after the onset of diabetes had increased insulin production and more beta-like cells when compared to controls.  Importantly, their blood glucose levels stayed in the normal range for about 4 months before returning to the diabetic range, indicating that the newly formed beta-like cells could evade immune attack during that time.  Also, the researchers were able to reprogram human alpha cells directly in cell cultures in the laboratory.  Human pancreatic islets isolated from male and female deceased donors were experimentally treated to destroy their beta cells and then treated with the Pdx1 and Mafa gene therapy.  When these reprogrammed islets were transplanted into an autoimmune diabetic mouse model, insulin production went up, and the mice had significantly better blood glucose control than similar mice given placebo-treated islets.

Overall, these results describe a new method to reprogram mouse pancreatic alpha cells to functionally replace destroyed beta cells.  The researchers cautioned that more research is needed to determine if this approach would work in people with type 1 diabetes, including whether human beta-like cells would survive for any length of time or if they would need extra protection against the ongoing autoimmune attack that occurs in type 1 diabetes.

References

Xiao X, Guo P, Shiota C,…Gittes GK.  Endogenous reprogramming of alpha cells into beta cells, induced by viral gene therapy, reverses autoimmune diabetesCell Stem Cell 22: 78-90.e4, doi: 10.1016/j.stem.2017.11.020, 2018.
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