The first patent for a method of delivering normal genes in a pill to induce
the production of insulin in people with diabetes was issued May 1 to the
University of California, San Francisco by the United States Patent and
Sometimes referred to as a “gene pill,” the oral delivery of normal genes has
been a long-sought and elusive technique. Now, UCSF researchers have
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
for insulin production, 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.
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 into muscles - including insulin, growth hormones, blood
factors for treating hemophilia, and erythropoietin for treating anemia.
Rothman expressed confidence that future patent awards to UCSF would cover
development of the method for many illnesses.
Genteric, 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
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
“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
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.”