An end to insulin injections could be realized within a decade for millions of diabetics, according to UCSF researchers.

UCSF scientists have developed a gene therapy strategy, applied in diabetic rats, to retool certain cells within digestive glands that already are capable of sensing blood sugar levels to produce and deliver insulin into the bloodstream and normalize blood sugar levels. The insulin-delivery process occurs automatically when food is eaten.

The nonsurgical procedure, reported today in the December issue of Nature Biotechnology, could also open up the door for treatment of other chronic diseases, including hemophilia, obesity and cancer, the researchers say.

"We initially targeted diabetes because there is a great need for a new type of therapy," says Ira D. Goldfine, MD, professor of medicine and physiology. "It is well-established that there are fewer long-term medical complications of diabetes when blood-sugar levels are kept normal, but keeping the blood sugar normal by the current methods of using injections or insulin pumps is a difficult task. Our data suggest that this new approach is a promising alternative."

The study was conducted in the laboratories of Goldfine, Michael S. German, MD, assistant professor of medicine; and Stephen S. Rothman, PhD, professor of physiology.

In the procedure, engineered genes are injected into the ducts of salivary glands and the exocrine pancreas. They then enter the exocrine cells, which produce the desired proteins -- insulin or human growth hormone.

These exocrine cells normally produce digestive enzymes that secrete into the digestive tract. However, previous research by UCSF's Rothman showed that exocrine cells of the pancreas and salivary glands also secrete substantial amounts of protein into the bloodstream.

The UCSF scientists designed a strategy that took advantage of these processes, manipulating the cells to produce and deliver the proteins insulin and growth hormone into the bloodstream.

Treatment of various human diseases with injectable proteins that are mass-produced by pharmaceutical companies is expanding. However, the UCSF strategy should enable the body to use its own protein factories to make the necessary proteins, eliminating the need for continual injections.

In the diabetic rats, the approach enabled the rats' own control mechanisms to regulate blood glucose levels, restoring them to normal concentrations.

"Protein secretion by the salivary glands and exocrine pancreas is regulated by a variety of hormones and neurotransmitter molecules," Rothman explains. "These regulatory molecules are among those that act on the islet cells that normally make and secrete insulin into the bloodstream as part of the feeding process."

Most prior attempts at gene therapy have used viruses to encase genes and ferry them into cells. But by taking advantage of the ductal route for the delivery of large molecules into cells, UCSF's German, a molecular biologist, was able to custom-design DNA packages that did not need viruses to gain entry.

The administration of non-viral DNA via glandular ducts helps evade the body's inflammatory immune response. With most gene therapy techniques, targeting the appropriate tissue for gene delivery is difficult, but with insertion of genes into ducts, precise delivery to the exocrine cells lining the ducts is achieved.

The UCSF researchers note that it will be simple to administer their therapy using procedures that are routinely used today in dentistry, gastroenterology, and radiology to diagnose diseases of the pancreas and salivary glands.

By Jeffrey Norris and Jennifer O’Brien

1st appeared 11/25/97

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