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Gene Editing May One Day Help Cure Some Cases of Type 2

By Andrew Curry , ,

Dieter Egli, PhD
Photo courtesy of Columbia University Irving Medical Center

Dieter Egli, PhD

Assistant Professor of Developmental Cell Biology at Columbia University

Stem Cells

American Diabetes Association Research Funding
Clinical or Translational

Beta cells are the body’s insulin factories. Found in the pancreas, they respond to blood glucose levels, churning out more insulin to signal muscle cells to absorb the glucose from the bloodstream.

In people with diabetes, beta cells don’t produce sufficient insulin. In people with type 2 diabetes, that’s because the beta cells fail over time. In people with type 1, the body’s immune system malfunctions and attacks the beta cells.

In some people with diabetes, beta cell failure is the result of faulty genes. Over the past decade, researchers have identified a handful of spots where a tiny mistake in a patient’s genetic code can interfere with the body’s ability to sense or produce insulin. The result is what doctors call monogenic diabetes.

Such single-gene mutations are responsible for more diabetes cases than generally recognized. Dieter Egli, PhD, a stem cell biologist at the Naomi Berrie Diabetes Center at Columbia University Medical Center in New York, says 1 to 5 percent of people with diabetes has some variety of monogenic diabetes, adding up to millions of people around the world. “It’s not such a rare phenomenon,” he says.

For decades, replacing failing beta cells has been the holy grail of treatment for all types of diabetes. Researchers have tried everything from pancreas transplants to beta cells surgically implanted in patients. But the replacement beta cells come at a high cost: Because they’re foreign cells, the body tends to reject them. Controlling the immune reaction requires powerful immunosuppressant drugs or encapsulation of the transplanted beta cells.

Because monogenic diabetes is the result of a single genetic flaw, or mutation, new technologies offer the promise of a cure for people with forms of monogenic diabetes. And the innovative treatment could perhaps lead to therapies for some type 2 patients. With the help of a grant from the American Diabetes Association, Egli and his team of scientists are working with monogenic diabetes patients—specifically, people with neonatal diabetes, whose inability to produce insulin appears at birth or shortly thereafter—to test a different approach. They start by creating stem cells, which are cells that can be shaped into specific tissues, from beta cells to nerves.

Then Egli uses a cutting-edge technique with the unwieldy name of CRISPR-Cas9 to fix the genetic mistakes that prevent beta cells from working. Over the past year, the research has yielded promising results. “We’ve been able to correct the mutation in stem cells and make insulin-producing beta cells,”  Egli says. “We showed, in principle, that it can be done.”

The next step would be to implant the corrected, lab-grown beta cells back into the patient. Because they’re grown from the patient’s own cells, they should be accepted by the body without the need for immunosuppressant drugs. And because they’re functional beta cells, they should respond to blood glucose levels and produce insulin the way normal beta cells do.

The science behind gene editing is still new, however, and not yet approved by the Food and Drug Administration (FDA) for testing in humans. To see if the beta cells worked, Egli took the corrected human beta cells and put them in lab animals bred to have beta cells that don’t work. “By grafting the beta cells into mice, we can protect beta cell–deficient mice from diabetes,” says Egli. “These are human cells that cure a mouse. It’s really something different.”

Egli says if the corrected beta cells can be safely implanted into a person with monogenic diabetes or even forms of type 2 that have a strong genetic cause, it would amount to a diabetes cure. “The beta cells will become part of the person,” he says.

Lots of work remains to be done before the gene editing techniques are ready to use in people. Some researchers worry that the techniques used to edit mutations could cause unintended, “off-target” effects elsewhere. “The mouse is a great model, but some answers we will only learn if we try them in humans,” Egli says.

Even if Egli and others in the field can prove that personalized gene therapy is safe, it will be a long time before it’s cost-effective compared with test strips, glucose meters, and insulin injections. While patients would no longer have to pay for insulin and other diabetes management supplies, personalized stem cell therapy could cost tens of thousands of dollars per patient, or more.

Egli is optimistic—particularly for people with no ability to produce insulin, such as the neonatal diabetes patients he is working with.

For now at least, so-called personalized gene therapy is easiest to apply in cases where problems producing insulin are the result of pinpoint errors that can be readily reversed, as with monogenic diabetes. However, Egli says he can imagine a future where more complex cases can also benefit from gene therapy: “Many people with type 2 may have mutations that are not well-characterized,” he says. Future research might identify cases where gene therapy could reduce type 2 risk. Likewise, stem cell–derived beta cells may one day be used to treat people with type 1 diabetes.

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