Reengineering Life is a series from OneZero about the astonishing ways genetic technology is changing humanity and the world around us.
In the 1990s, a handful of people with Type 1 diabetes underwent an experimental therapy in hopes of curing their disease. They received transplants of tissue containing insulin-producing cells from people who had recently died. The hope was that the cells in the donor tissue would make up for the recipients’ faulty ones.
These insulin-producing cells, known as beta cells, are damaged or depleted in the more than 34 million people in the United States — about 10% of the population — who have diabetes. Beta cells normally produce and release insulin, a hormone that regulates blood sugar. But without these cells, people with diabetes need to take insulin regularly.
The transplants worked — temporarily, at least. Some patients no longer needed regular injections of insulin, but the effects wore off after a few months or years. The recipients also needed to take harsh immunosuppressant drugs so their bodies wouldn’t reject the transplanted tissue.
The therapy is far from ideal, but scientists haven’t given up on the idea of using beta cells to treat diabetes. Now, they think CRISPR could improve upon the idea.
Researchers at Washington University in St. Louis, where some of the first of these transplants occurred, recently used CRISPR to correct stem cells from diabetic patients and turn them into fully functioning beta cells. After transferring the edited cells into mice with diabetes, the animals’ blood sugar normalized. The results were published in the journal Science Translational Medicine on April 22.
Though the work was done using cells from patients with a rare form of the disease, the authors think the approach could eventually be used to treat Type 1 and Type 2 diabetes.
“We were able to reverse the diabetes in the mice in about a week,” Jeffrey Millman, an assistant professor of medicine and biomedical engineering, tells OneZero. Several years ago, Millman and his colleagues discovered how to convert human stem cells into pancreatic beta cells that make insulin.
For the new study, Millman and his colleagues worked with Dr. Fumihiko Urano, an endocrinologist at Washington University Medical Center and expert on a rare form of diabetes called Wolfram syndrome, which causes childhood diabetes and deafness. Urano had taken skin cells from a patient with the condition and used them to generate a type of stem cell that can be turned into any cell type in the body, called induced pluripotent stem cells. Using CRISPR in those stem cells, they corrected a mutation in the gene that causes the disease. They then transformed the corrected stem cells into pancreatic beta cells and injected them into mice. After a week, the animals’ blood sugar levels had become normal and remained that way for the entire six months they were monitored.
The results are promising, but there are a number of questions that remain about how to apply the approach in people. For one, scientists don’t yet know the best location in the body to infuse the corrected beta cells. In some previous clinical trials using beta cells from donors, doctors have tried infusing cells underneath the skin, but the technique didn’t work that well.
Another issue is that scientists need to generate a lot of cells in order to treat a patient. Millman says it would probably take around the order of a billion cells. That could be a long process, taking several months or up to a year.
Then there’s the matter of how to use this approach to treat Type 1 and Type 2 diabetes as opposed to the rare type of diabetes Millman and his team studied. It would hinge on patients getting genetic testing so doctors could identify the genetic mutations responsible for their diabetes. “There have been dozens of mutations that have been identified as being associated with increased risk of Type 1 and Type 2 diabetes, and many of these are genes that are expressed in the beta cell,” Millman says. In the future, he says CRISPR could be used to correct certain mutations in beta cells from those patients.
But unlike Wolfram syndrome, which results from a single genetic mutation, the vast majority of diabetes cases arise from a mix of genetic and environmental factors. So, many more edits would be needed in order to correct beta cells from these patients.
If the treatment works, it could be a long-term fix for diabetes, and because the approach uses a patient’s own cells, it would eliminate the need for transplant recipients to take immunosuppressant drugs. It could also stave off the potentially serious health complications that arise from diabetes, like nerve and kidney damage, obesity, heart attack, and stroke. But because the process of generating cells would need to be tailored to individual patients — a very time-consuming effort — it would be difficult to make these cells for every person with diabetes.
It’s also a complicated treatment that combines two experimental technologies. The first U.S. clinical trial that uses induced pluripotent stem cells just got underway in December, and studies using CRISPR in people are still in their early stages.
But despite the technical hurdles, the idea of editing stem cells with CRISPR has already attracted interest from biotech companies. CRISPR Therapeutics, for one, has partnered with ViaCyte to develop a gene-edited stem cell therapy for diabetes. But in contrast to the work being done at Washington University, their method uses stem cells derived from a human cell line, which could be grown indefinitely, rather than from the patients intended to receive the therapy. This method wouldn’t require correcting the different genetic mutations that cause diabetes in individuals and therefore could be scaled up a lot faster.
To make sure the transplanted cells don’t get rejected by the body, the companies are editing them with CRISPR to evade detection by the immune system. This would eliminate the need for immunosuppressant drugs. The therapy hasn’t yet been tested in people.
Though CRISPR-edited stem cells aren’t likely to replace insulin anytime soon, we could see the first human trials of them in a few years.