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Bursting the Bubble on Diabetes

Research with rats points the way to delivering gene therapies for diabetes using tiny bubbles and ultrasound.

One of the biggest challenges to using gene therapy for treating or curing diseases is finding a way to deliver genes safely into the cells where they’re needed. Now a study in Proceedings of the National Academy of Sciences shows that a combination of ultrasound and tiny bubbles can deliver genes into the insulin-producing cells of rats. It’s a technique that could someday be used to help treat diabetes.

Introducing new genes into cells has the potential to correct defects in several major diseases, including cystic fibrosis, cancer, and cardiovascular disease. But cells do not easily take up foreign genes. So gene therapy has resorted to using delivery systems such as viruses, which can potentially cause a dangerous immune response.

In this new approach, called “ultrasound targeted microbubble destruction,” researchers at Baylor University Medical Center in Dallas coated small gas-filled bubbles with DNA, and injected them into the bloodstream. They then directed an ultrasound beam to the target region of the body – in this case, areas in the pancreas called islets responsible for producing insulin. The ultrasound waves caused the bubbles in nearby blood vessels to burst, releasing the genes in the bubbles, while breaking holes in the membranes of adjacent cells, thereby creating a passage for the genes to enter through.

In the experiments described in the recent study, the Baylor team, working with researchers at University of Texas Southwestern Medical Center and Duke University, used the technique to deliver the human insulin gene to the islets of rats. Human insulin could be detected in the animals’ blood several days later, and the animals’ blood sugar levels dropped compared with rats that received a sham therapy.

The advantage of this approach is that the treatment can be given with a simple injection, yet it affects only the region exposed to ultrasound. “This work shows that genes can be targeted to pancreatic islets in living, adult animals,” says Paul Grayburn, the cardiologist at Baylor University Medical Center who led the study in collaboration with colleagues at the Baylor Institute of Metabolic Disease.

Diabetes comes in two major forms. In type 1 diabetes, the immune system attacks and destroys the islets. In type 2 diabetes, the body either does not produce enough insulin or becomes resistant to it. Without proper insulin function, blood sugar levels rise, leading to health problems and even death. Gene therapy is seen as especially promising for type 1 diabetes, either to restore insulin production in remaining islets or to protect them from immune attack. Less is known about the origin of type 2 diabetes, but research has begun to uncover genes involved in the disease that might be targeted.

Microbubbles are already approved for use with ultrasound as a diagnostic tool. They’re injected into the blood stream and then exposed to a frequency that causes them to oscillate, which makes them highly visible in ultrasound images. Over the past decade, several research groups have explored a variation of the technology, coating the bubbles with drugs or genes and making them burst, as a new therapeutic method. Grayburn and his colleagues, for example, previously tested this approach as a way to deliver a gene that encourages the growth of new blood vessels in the heart.

However, the approach has a long way to go before it’s a feasible treatment. One key problem is duration. In this study, the protein produced by the new gene was detected for only about three weeks after treatment. “The biggest challenge is to create something that lasts a long time,” says Katherine Ferrara, a biomedical engineer at University of California, Davis. “It’s hard to imagine someone would want to repeat this treatment over and over again.”

Nick Giannoukakis, an immunologist at University of Pittsburgh School of Medicine, who has been working on several experimental therapies for type 1 diabetes, says the approach is interesting, but the key question is “What does this do to diabetes?” He says the delivery system must be shown to reverse or ameliorate diabetes in animals before its potential as a treatment can be judged. Grayburn says that he and his collaborators are working with diabetic animals to answer that question.

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