Diabetes Vaccine Shows Promise In Early Trials
June 27, 2013

DNA Vaccine May One Day Fight Type 1 Diabetes

April Flowers for redOrbit.com - Your Universe Online

Researchers at Stanford University School of Medicine are leading an international team of scientists in a clinical trial of a vaccine designed to combat type 1 diabetes. The vaccine has delivered initially promising results, leading the team to suggest it may selectively counter the errant immune system response that causes the disease.

The study, which will be published in an upcoming issue of Science Translational Medicine, was a multicenter, randomized, double-blind trial that produced several key findings. For example, levels of a blood-borne proxy of insulin production were maintained, and in some cases increased, over the course of the 12-week dosing regimen, indicating those getting the vaccine may have suffered less ongoing destruction of beta cells than those given placebo injections. Beta cells produce and secrete the peptide (short protein sequence) hormone insulin after a meal.

Another finding in patients receiving the vaccine involves blood levels of a specific group of immune cells that inappropriately hone in on and destroy a protein found only on beta cells. These immune cells appear to have been selectively depleted in these patients. No adverse effects, serious or otherwise, that could be caused by the vaccine were observed.

"We're very excited by these results, which suggest that the immunologist's dream of shutting down just a single subset of dysfunctional immune cells without wrecking the whole immune system may be attainable," said Lawrence Steinman, MD, professor of pediatrics and of neurology and neurological sciences at Stanford. Steinman is an immunologist and multiple sclerosis specialist at Lucile Packard Children's Hospital. "This vaccine is a new concept. It's shutting off a specific immune response, rather than turning on specific immune responses as conventional vaccines for, say, influenza or polio aim to do."

Steinman cautions these results are preliminary and that longer and larger studies are needed to validate the findings. No DNA vaccine has been approved for human use to date, and any likely application of this vaccine is years away. The study reports the vaccine's observed beneficial effects began to drop off a few weeks after the 12-week vaccine-dosing schedule was discontinued.

As Reuters reports, this is not the first attempt to manipulate the immune system to stop the destruction of insulin-producing cells that are responsible for type 1 diabetes, which affects as many as three million Americans.

Prior studies have attempted to suppress desirable parts of the immune system, leaving participants vulnerable to infections and cancer.

"What one really wants to do is tame or regulate the specific aspects of the immune system that have gone awry and leave the rest of the immune system intact," said Dr. Richard Insel, chief scientific officer of JDRF, formerly known as the Juvenile Diabetes Research Foundation.

The current study involved 80 type 1 diabetes patients who were receiving insulin injections. The goal was to test the safety of the vaccine, TOL-3021, which is made up of a small round piece of DNA called a plasmid that is genetically engineered to tamp down the immune response to insulin and preserve insulin-producing beta cells. The DNA vaccine targets proinsulin, a precursor protein in the blood.

"It's a complicated series of snips and cuts in the DNA that take away the capability to stimulate the immune system," Steinman said. "This effectively triggers an off-switch."

The way a typical vaccine works is to deliver proteins (or groups or sections of them) in a manner intended to fire up the immune response against, say, infectious organisms to which those proteins are unique. TOL-3021, on the other hand, consisted of DNA containing, instead, the gene coding for the proinsulin protein. In contrast to traditional vaccines again, TOL-3021 was not designed to beef up the immune response to proinsulin, but to shut it down.

To create the vaccine, the researchers tweaked a piece of DNA containing the proinsulin gene in a way that, they predicted, would cause a special class of immune cells ingesting the vaccine to deliver an anti-inflammatory signal to CD8 cells targeting proinsulin, and to those cells alone. CD8 cells are patrolling immune cells that attack cells displaying suspicious peptide fragments.

Modified genetic material was incorporated into rings of DNA and administered through weekly instramuscular injections for 12 weeks. Four different doses of the vaccine were given to four patient groups, while placebo injections were given to a fifth group. The placebo recipients were given the option of undergoing a 12-week regimen of weekly dosing with the vaccine after the conclusion of the trial.

Tolerion has licensed rights to the vaccine from Stanford, and is planning a longer study in as many as 200 patients, testing whether the vaccine can slow or stop progression of the disease in younger patients, before too much damage has been done.

The ultimate hope is to develop a vaccine that could be given to individuals who are genetically predisposed to develop the condition.