New drug may prevent progression of type 1 diabetes

Susan Jeffrey

March 30, 2004

Tue, 30 Mar 2004 19:30:00

Cambridge, UK - Researchers are reporting that after 18 months of follow-up, patients with adult-onset type 1 diabetes are still producing their own insulin after being treated with a protein called glutamic acid decarboxylase (GAD65) formulated as a vaccine, basically inoculating them against the autoimmune attack on insulin-producing beta cells. Insulin production was not only preserved but improved in treated patients.

The 18-month phase 2 results were presented during an invited lecture at the International Diabetes Society meeting. Six-month results were presented in June 2003 at the American Diabetes Association meeting.

"Eighteen months is a long time to preserve the ability to make insulin in these patients," Dr Daniel L Kaufman (University of California, Los Angeles) told heartwire . "If this drug is able to inhibit the autoimmune response and preserve the cells that make insulin at such a late stage in the disease process, then we and the company (Diamyd Medical, Stockholm, Sweden) are very hopeful that, when allowed to treat children at earlier stages of the disease, it will be even more efficacious in terms of preventing the disease onset."

The phase 2 study was carried out by researchers at Diamyd after they licensed the drug from UCLA.

Vaccination against autoimmune attack

In type 1 diabetes, studies have now shown that a major antigen for the autoimmune attack on insulin-producing beta cells is a protein called GAD65, the researchers note. GAD autoantibodies are present at diagnosis and have been shown to predict development of the disease.

In 1993, Kaufman and colleagues showed in diabetes-prone mice that by giving small amounts of the GAD protein, they could create tolerance to the protein in these animals, inhibiting the autoimmune attack and the development of diabetes. In 1996, they published findings showing that the progression of type 1 diabetes could be prevented in these mice even though the disease process had already begun.

Although type 1 diabetes mainly affects children and teens, about 10% to 15% of people with the disease are diagnosed as adults, a condition referred to as latent autoimmune diabetes in adults (LADA). When patients with type 1 diabetes present with hyperglycemia, they usually still have some residual ability to make insulin, Kaufman said. "What this study did was ask whether they could preserve the little bit they still made and preserve it longer than in other people who would inevitably just lose their ability to make insulin," Kaufman said.

The phase 2 study included 47 adult patients recently diagnosed with LADA and having autoantibodies to GAD, at the UMAS Hospital in Malmö and St Gorans Hospital in Stockholm. Patients were randomized to one of four groups; nine patients in each group received injection with alum-formulated GAD65 in doses ranging from 4 to 500 g, and three received alum alone as a placebo. Each subject received a first injection, followed by at least one boost injection four weeks later.

Six-month study results, presented in June 2003 at the American Diabetes Association meeting, showed that treatment significantly improved serum levels of C-peptide, a metabolite of endogenous but not exogenous insulin, both fasting and after meals. Now, Kaufman said, "their C-peptide levels actually improved a little bit and stabilized over 18 months."

The Diamyd researchers also correlated positive responses to increases in CD4+CD5+ cells that suppress autoimmune response; those with the greatest increase in these cells had the most improvement in long-term insulin production.

The company plans to "seek cooperation with established pharmaceutical companies for further development" and is pursuing other GAD-based projects, "of which the GAD-based diabetes vaccine, Diamyd®, is the most advanced at this time," according to a press statement posted to its website when the six-month results were released. Future studies will look to see whether the vaccine will work in young patients who have not yet developed the disease but who have antibodies to GAD.

Serendipity at work

Making the connection between GAD in the brain and in the pancreas wasas many scientific discoveries areserendipitous. In the mid-1980s, Kaufman was a graduate student working on cloning genes for neurotransmitters. As part of his graduate work, his group cloned a gene called GAD, the protein product of which is involved in the production of a particular neurotransmitter. They also knew it was produced in the pancreas, although at the time thought little of it.

Later, stuck at the lab one day when his car broke down, Kaufman was flipping through an issue of the New England Journal of Medicine. "It fell open by accident to this one article by somebody who is now my close colleague, Dr Mark Atkinson (University of Florida, Gainesville)," Kaufman says. The article described a new way to predict who would get type 1 diabetes by measuring titers of an antibody to a protein in insulin-producing cells. The researchers had not yet identified the protein but knew its molecular weight, which was similar to that of the GAD protein. "I put two and two together and began to ask, is what's being attacked here my favorite protein? And in fact it was," he says. Knowing the protein target has led to a variety of diagnostic tests that can identify those who will go on to develop type 1 diabetes by detecting antibodies against GAD. However, while the test has been very important for researchers, it hasn't yet been developed for public use. "Without a therapeutic, there's not much reason to push the diagnostic," Kaufman says.

They began trying to develop interventions that might be clinically relevant. "When we showed in 1996 that we could prevent mice from getting diabetes by giving them GAD in this way, it was licensed to Diamyd," he said. "It's very gratifying to see it go from the lab bench to the clinic."


Related links


2. [HeartWire > News; Mar 18, 2004]

3. [HeartWire > News; Mar 08, 2004]

4. [HeartWire > News; Mar 07, 2004]


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