One of the holy grails of diabetes research – reversing Type 1 diabetes without the use of immune-suppressing drugs – may have gotten a little bit closer with a study that used gene therapy to reprogram some pancreatic cells so that they became insulin-producing cells.
The researchers were able to reverse Type 1 diabetes in mice for up to four months and say they believe it could last considerably longer in humans.
“We have shown for the first time that gene therapy can be specifically and effectively targeted to reverse autoimmune diabetes in mice without the use of any immunosuppressant drugs,” said George K. Gittes, the senior author of the study. Gittes is chief of pediatric surgery at the University of Pittsburgh School of Medicine and the Benjamin R. Fisher Chair in Pediatric Surgery at Chilren’s Hospital of Pittsburgh. The study was jointly conducted by researchers at the two facilities, and published last week in the journal Cell Stem Cell.
Mouse studies on therapies for diabetes have a history of frequently not translating well to humans, in large part because of the many differences in the immune systems of the two species. The problem is so common that it’s led to the saying that “mice lie,” and a 2016 report in the journal Diabetes on the phenomenon was titled “How to Make Mice Tell the Truth.”
But Gittes said his team is now using the therapy on primates with promising results, and he hopes to get permission soon to begin Phase One trials on humans. The therapy could be useful for Type 2 diabetes as well, he said.
Type 1 diabetes attacks the beta cells of the pancreas, which in healthy people produce insulin. Using a bioengineered virus often employed in gene therapy as a genetic carrier, Gittes and his team introduced two genes into pancreatic alpha cells, reprogramming them to produce insulin and bringing blood glucose to normal levels. The genetic cocktail was delivered directly to the pancreas via endoscopy, allowing researchers to use a much smaller amount of virus than with traditional gene-therapy injections and reducing the chances for side effects. The genetically-altered virus has been robbed of its ability to sicken people but retains the ability to gain entry to cells and modify their DNA.
“This method to deliver a gene therapy directly to the pancreas could easily be applied to humans, as similar pancreatic injections are routinely performed as part of a non-surgical endoscopy procedure,” Gittes said.
Over time, however, the the immune system attacked the newly programmed cells as well. The treatment could still be useful, however, if the cells last longer in humans, though repeated treatments would probably still be necessary.
The Pittsburgh study comes just two months after researchers in Boston successfully used another form of gene therapy against diabetes in mice. Writing in the November 15 issue of the journal Science Translational Medicine, researchers at Boston Children’s Hospital described work in which of the used a bioengineered to insert genetic material into the blood stem cells of mice.
“We found that in diabetes, blood stem cells are defective, promoting inflammation and possibly leading to the onset of disease,” senior investigator Paolo Fiorina said in a post published by the hospital. Specifically, both mice and humans with diabetes have difficulty producing amolecule called PD-L1 that helps regulate inflammatory response. The mice were injected with blood stem cells with a healthy gene for PD-L1.
Almost all of the treated mice were cured of diabetes – though, again, the effects were largely temporary. One-third of the mice did remain diabetes-free for the rest of their lives.
“There’s really a reshaping of the immunse system when you inject these cells,” Fiorina said.