Normal Glucose Levels Restored via Gene Therapy in Mice with Type 1 Diabetes

Edward Kim  |

Scientists at the University of Pittsburgh School of Medicine have shown that gene therapy can lead to the long-term survival of functional insulin-producing cells as well as normal blood glucose levels for an extended period of time in mice with diabetes. The study was published online today at Cell Stem Cell, and was led by George Gittes, MD, Chief of the Division of Pediatric Surgery and Director of Surgical Research at Children’s Hospital of Pittsburgh of UPMC.

The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells. In patients with type 1 diabetes, the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose.

Human stem cell-derived beta cells that have formed islet-like clusters in a mouse (

Douglas Melton, courtesy of Harvard University, via the National Institutes of Health)


This study is essentially the first description of a clinically translatable, simple single intervention in autoimmune diabetes that leads to normal blood sugars, and importantly with no immunosuppression," "A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy.

- George Gittes, MD

A fundamental goal of diabetes treatment is to preserve and restore functional beta cells, thereby replenishing the body's insulin, which moves blood glucose to fuel cells. In patients with type 1 diabetes, however, beta-cell replacement therapy is likely doomed to failure because the new cells might fall victim to the same autoimmunity that destroyed the original cells.

A potential solution to this problem is to reprogram other cell types into functional beta-like cells, which can produce insulin but are distinct from beta cells and therefore are not recognized or attacked by the immune system. To explore the feasibility of this approach, Dr. Gittes and first author Xiangwei Xiao, MD, PhD, Assistant Professor of Surgery at the University of Pittsburgh, engineered an AAV vector to deliver to the mouse pancreas proteins called Pdx1 and MafA, which support beta cell maturation, proliferation and function. The goal was to generate functional beta-like cells from pancreatic alpha cells, which may be the ideal source for beta cell replacement, as alpha cells are plentiful, resemble beta cells, and are in the correct location, all of which could facilitate reprogramming.

By comparing the gene expression patterns of normal beta cells and insulin-producing cells derived from alpha cells, the researchers confirmed nearly complete cellular reprogramming. This gene therapy approach restored normal blood glucose levels in diabetic mice for an extended period of time, typically around four months, and the new insulin-producing cells derived almost exclusively from alpha cells. Moreover, the strategy successfully generated functional insulin-producing cells from human alpha cells.

Several features of this approach could facilitate translation to humans. AAV vectors like those used in this study are currently undergoing various gene therapy trials in humans, and the viral vectors can be delivered directly to the human pancreas through a routinely performed non-surgical endoscopic procedure. Though this procedure can elicit pancreatic inflammation, no immunosuppression is required, so patients would avoid related side effects such as an increased risk of infection.

One major concern was that the mice did eventually return to the diabetic state, suggesting that this treatment would not represent a definitive cure for the disease. Currently, the researchers are testing their approach in primates.

The protection from recurrent diabetes in the mice was not permanent, although some studies would suggest that processes in mice are highly accelerated, so four months in mice might translate to several years in humans. If we are able to show efficacy in non-human primates, we will begin work with the FDA to get approval for the use of this viral gene therapy in diabetic patients, both type 1 and type 2.

- George Gittes, MD

The researchers were supported by National Institutes of Health, the Juvenile Diabetes Research Foundation, the Children's Hospital of Pittsburgh, and the University of Chicago.

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