You may not have heard of GAD, but it’s a hot topic in the world of type 1 diabetes research. GAD, which stands for glutamic acid decarboxylase, is an enzyme in the brain and the pancreas that plays several roles in the body. As an enzyme, it converts the excitatory amino acid glutamate into the inhibitory neurotransmitter GABA, which nerve cells use to communicate. But it also has a less helpful role, as an autoantigen (an element of self that provokes the generation of antibodies) in autoimmune diabetes.
Antibodies are a part of the immune system’s response to foreign invaders. In type 1 diabetes, certain T lymphocytes, also known as T cells, mistakenly identify the insulin-producing beta cells in the pancreas as enemies, leading to the production of antibodies against them. The result of this misdirected attack is that the beta cells are destroyed and the body can no longer produce sufficient insulin.
Most people with type 1 diabetes have antibodies to GAD. Some people without type 1 also have antibodies to GAD, the presence of which predicts a higher likelihood of future development of type 1 diabetes. But perhaps the most interesting of GAD’s many attributes is that when given as a therapeutic, it seems to intervene in the disease process that causes type 1 diabetes.
GAD has been studied by scientists around the world since the 1970s, when it was first discovered that type 1 diabetes is an autoimmune disease. In 1975, researchers in England detected antibodies to pancreatic islet cells in people with newly diagnosed type 1 diabetes. These came to be called islet cell antibodies, or ICAs. In the late 1970s and early 1980s, Dr. Ake Lernmark, who had been researching proteins on the surface of beta cells, discovered antibodies to a certain protein in the plasma of Swedish children with type 1 diabetes. Because the protein weighed 64 kilodaltons, it was called the mystery 64K protein. This discovery led to further research on diabetic rats and then on humans, revealing that these 64K antibodies are an early warning sign of the eventual development of diabetes.
In 1990, in a major breakthrough, scientists identified the 64K protein as GAD. Two graduate students at UCLA, Daniel Kaufman and Mark Erlander, had been studying genes involved in neurological diseases and neuronal development in the brain. They were the first to isolate the gene encoding GAD. They did not yet know, however, that GAD was also made in the beta cells of the pancreas and involved in the type 1 diabetes disease process.
Dr. Kaufman became interested in a possible diabetes connection when his car broke down one day and he found himself marooned at the library. While waiting for his car to be repaired, he stumbled onto an article in the British medical journal The Lancet, written by Dr. Mark Atkinson of the University of Florida. In it, Atkinson described 64K antibodies as early predictors of type 1 diabetes.
Kaufman thought that the 64K protein might be the GAD he had studied in connection with brain chemistry. He and his associates tried to establish a connection between GAD and diabetes and, sure enough, they learned that they could detect antibodies against GAD years before overt symptoms of diabetes appeared.
Next, they researched ways to make the immune system of diabetes-prone mice tolerant of the GAD protein before the autoimmune attack began. They found that by administering GAD to the mice in a vaccine-like manner, they could prevent the onset of diabetes. Their results were published in 1993, in the prestigious scientific journal Nature. In 1996, it was shown that even after the autoimmune attack had started in mice, it could be stopped with GAD vaccination.
So how does GAD work as a therapeutic in autoimmune diabetes? According to theory, it activates a subset of T cells that recognize GAD as self rather than invader. The T cells travel to the pancreas, where they calm down the immune cells that were killing the beta cells, thereby preserving their insulin-producing capacity.
What makes GAD different from other immune-suppressant drugs (which are also under development for beta cell preservation) is that it is a highly targeted substance which activates only the immune cells that recognize GAD. Because GAD modulates the immune response very specifically and does not affect the immune system in general, it is actually known as an immune modulator rather than an immune suppressant.
In 1994, UCLA licensed its GAD technology to Diamyd Medical, a Swedish diabetes company, for pharmaceutical development. The GAD gene was cloned to produce highly purified recombinant GAD for further development as a therapeutic called Diamyd GAD. Later on, clinical studies were carried out with Diamyd GAD in LADA patients. (Latent autoimmune diabetes in adults, or LADA, also known as type 1.5 diabetes, generally occurs after age 35.) The patients who received the GAD treatment were able to preserve some insulin production for several years after the study.
A larger Phase 2 research study was subsequently conducted in which 70 newly diagnosed children and adolescents with type 1 diabetes were followed for 30 months after two injections of either Diamyd GAD or a placebo. The study was double-blind, meaning that neither the researchers nor the subjects knew who received the placebo and who was given the Diamyd GAD. The children who received the GAD, however, experienced a statistically significant effect with regard to preservation of insulin secretion, and no adverse side effects were observed. The results of that study were published in The New England Journal of Medicine in 2008.
Just recently, a European Phase 3 trial involving Diamyd GAD with 320 children and adolescents in nine EU countries completed enrollment. Results are expected in the spring of 2011. At this time, recruitment continues here in the U.S. on the nationwide DiaPrevent diabetes research study, a parallel Phase 3 trial. Over thirty clinical sites across the U.S. are participating.
Trial Net, an NIH-sponsored international network of researchers investigating ways to prevent, delay, and reverse type 1 diabetes, has also been using GAD since 2009, in one of its U.S. studies involving beta cell preservation.
Now, with enough data collected on the safety and efficacy of Diamyd GAD, testing it as a vaccine to prevent type 1 diabetes in children has also begun. The first Swedish children at high risk for developing type 1 diabetes were vaccinated this past year and are being followed to see if they develop the disease or not. Large scale prevention studies are being planned and will hopefully follow soon.
The researcher Ake Lernmark, who was the first to demonstrate the presence of antibodies against GAD in autoimmune diabetes, has even higher hopes for GAD. “Will the story of GAD,” he says, “end with preventative treatment for type 1 diabetes? Hardly! We want to cure as well.”
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To learn more about the DiaPrevent diabetes research study taking place in the U.S. for newly diagnosed children aged 10 to 20 years, visit www.diaprevent.diamyd.com.