The technique holds the potential for providing patients with more than 50 proteins normally secreted by the body into blood and which patients now receive by injection - including insulin, growth hormones, blood factors for treating hemophilia, and erythropoietin for treating anemia.
Sometimes referred to as a "gene pill," the oral delivery of normal genes has been a long-sought and elusive technique. In order to receive patent rights to their method, UCSF researchers successfully demonstrated that raw DNA taken orally can find its way inside cells lining the intestinal tract and prompt those cells to express a protein, such as insulin, even though they are not specialized for that purpose.
"Considerable work still needs to be done before there is an actual gene pill, but the patent demonstrates the validity of the concept and promises to spur development of oral delivery of genes to treat a vast number of illnesses," said Stephen S. Rothman, PhD, professor of physiology in the UCSF Schools of Medicine and Dentistry.
Rothman noted that the patent office acted rapidly to issue the second patent announced today to include all secreted proteins (US Patent 6,258,789).
Genteric Inc., a biotechnology company in Alameda, Calif. has an exclusive, worldwide license agreement with the University to use the method for drug development. The inventors of the technique - Rothman; Michael S. German, MD, associate professor of medicine in the UCSF Hormone Research Institute; and Ira Goldfine, MD, UCSF professor of medicine - along with Michael H. Nantz, PhD, professor of chemistry at UC Davis, are the founders of Genteric.
The research team began studying the technique at UCSF five years ago with funding from the UCSF Foundation and formed Genteric three years ago to pursue practical applications.
Oral delivery of genes differs from many of the highly publicized gene therapy techniques now under investigation in clinical trials at research centers across the country. Gene therapy in those studies attempts to correct disease at its root by administering DNA to cells through the use of a modified virus or other microscopic delivery vehicle in order to provide a permanent or long-term cure or treatment for the disease.
Oral delivery of genes is intended to provide short-term therapy by placing a specifically-engineered therapeutic gene with normal DNA in cells lining the intestinal tract, causing those cells to express a desired protein to be secreted into the blood - in the case of this patent, insulin. Cells containing the therapeutic gene would continue to express the protein only for the few days they remain on the wall of the intestine before the body routinely sloughs them and replaces them with new cells. In effect, the therapeutic genes would remain "outside" the body on the surface of the gastrointestinal tract as they pass through the body, even as the protein drugs that are manufactured are released into the blood stream. As a consequence, the genes pass relatively quickly through the body creating less opportunity to access the blood stream or to enter other cells, including those in the ovaries or testes.
"Regular oral delivery of new genes would provide continuous production of insulin, and the natural removal of the affected cells would permit doses to be adjusted or stopped easily," said German, an expert on diabetes.
To demonstrate the validity of the method, the UCSF research team had to show, among other obstacles, that neither stomach acids nor intestinal enzymes would destroy the DNA.
"People thought the oral delivery of genes might be possible in some vague, general way, but few believed it would really work," said Rothman, who serves as chair of the scientific advisory board for Genteric. "That barrier has been overcome. We have shown that proteins from genes administered orally are secreted into the blood stream."
The UCSF researchers demonstrated that orally administered genes induce the secretion of proteins through a series of studies involving laboratory rats. In the first step, they injected the genes produced through genetic engineering directly into isolated intestinal loops in anesthetized rats. They then were able to measure increases in proteins such as growth hormone in the blood stream.
The research team later duplicated the successful results by placing a catheter into the upper portion of the intestine and injecting daily doses of genes. Finally, it was shown at Genteric by placing the genes directly into the animals' stomachs through a feeding tube. Together, the studies produced evidence that the technique resulted in the secretion of growth hormone and insulin, and the production of luciferase - a luminescent marker protein.
"It needs to be emphasized that this is early stage technology, which is still some years from clinical application," Rothman said. "Nevertheless, it demonstrates the validity of the concept and promises to spur the development of the oral delivery of genes to treat many illnesses."