Approximately 9% of the world’s adult population has diabetes. The disease can cause serious health problems such as heart disease, nerve damage, eye problems, and kidney disease. Type 1 diabetes specifically is a chronic disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, which results in high glucose blood levels.
Treatments for diabetes are aimed at preventing and restoring functional beta cells because by doing so, it replenishes the levels of a hormone called insulin. Insulin is what moves blood glucose into cells to fuel their energy needs. The problem with beta-cell replacement therapy (treatment) for patients with type 1 diabetes is that it is likely doomed to failure because the new cells might fall victim to the same autoimmunity that destroyed the original cells.
Now, with gene therapy, scientists may have found a way. A recent study found that a gene therapy approach can lead to the long-term survival of functional beta cells as well as normal blood glucose levels for an extended period of time in mice with diabetes. The scientists used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins – Pdx1 and MafA. These proteins reprogrammed plentiful alpha cells into functional, insulin-producing beta cells. The research has been published in Cell Stem Cell.
Senior study author George Gittes of the University of Pittsburgh School of Medicine said:
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.
A possible route around the problem involved reprogramming 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. Gittes and first author Xiangwei Xiao decided to test this solution out. They engineered an AAV vector to deliver to the mouse pancreas proteins called Pdx1 and MafA, which support beta cell maturation, proliferation, and function. Their aim was to generate functional beta-like cells from pancreatic alpha cells – a potentially ideal source for beta cell replacement because alpha cells are plentiful, resemble beta cells, and are in the correct location, all of which could facilitate reprogramming.
Next, the researchers confirmed nearly complete cellular reprogramming by comparing the gene expression patterns of normal beta cells and insulin-producing cells derived from alpha cells. This confirmation revealed that the gene therapy approach had restored normal blood glucose levels in diabetic mice for an extended period of time, typically around four months, and the new insulin-producing cells were derived almost exclusively from alpha cells. To top it off, the strategy successfully generated functional insulin-producing cells from human alpha cells.
Gittes said:
The viral gene therapy appears to create these new insulin-producing cells that are relatively resistant to an autoimmune attack. This resistance appears to be due to the fact that these new cells are slightly different from normal insulin cells, but not so different that they do not function well.
There are many aspects of their research which facilitate translation of this treatment to humans. For instance:
- AAV vectors like those used in this study are already undergoing various gene therapy trials in humans.
- The viral vectors can be delivered directly to the human pancreas through a routinely performed non-surgical endoscopic procedure. (Although, this procedure can elicit pancreatic inflammation.)
- No immunosuppression is required. (Meaning patients would avoid related side effects such as an increased risk of infection.)
There is one downside to the discovery however, the mice did eventually return to the diabetic state, suggesting that this treatment would not represent a definitive cure for the disease. Gittes said:
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.
At the moment, the scientists are testing their approach in primates. Gittes said:
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.
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