Vaccine for Type 1 Diabetes Shows Promise : Swedish biotech company signs development and marketing deal with Johnson & Johnson.
Ideally, a combination therapy should be multipronged, with three goals: Stop immune destruction, preserve beta-cell mass, and replace or regenerate beta cells. Such a regimen might start off with a potent anti-inflammatory therapy – perhaps an anti-interleukin-1beta agent or tumor necrosis factor inhibitor – to quell the metabolic stress surrounding the pancreatic islets. This might well need to be given on a continuing basis.
Dr. Ludvigsson reported receiving research grant support from Diamyd. Dr. Skyler has served as a consultant to and/or received research grants from numerous pharmaceutical companies.
'It's too early to say if this works. Absolutely too early.'
Source DR. LUDVIGSSON
Eventually, fasting C-peptide levels start to fall off in parallel to the placebo group.
Source DR. SKYLER
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More Than One Type of Prevention
Elimination of the environmental agent(s) responsible for type 1 diabetes (T1D) would be the most efficient approach to primary prevention; however, more work is needed to identify the environmental agents and to develop effective interventions.
Blocking progression from islet autoimmunity to clinical diabetes or secondary prevention has been attempted, so far to no avail, by a number of groups, including large randomized trials.
Trials in patients with newly diagnosed T1D aim at tertiary prevention, such as preservation of remaining islet beta cells to induce and prolong partial remission. Unfortunately, most islets have already been destroyed by the time diabetes is diagnosed and complete reversal of diabetes is highly unlikely. Benefits may include a simpler insulin regimen, lower hemoglobin A1c, and reduced risk of hypoglycemia and microvascular complications. The gain may be even greater if the intervention is applied as soon as the patient shows asymptomatic “dysglycemia.”
While new interventions are often tested first in patients with established diabetes, and, when proven safe, applied to patients with pre-T1D, efficacy after diagnosis of diabetes is not to be a precondition to application in pre-T1D, as there may be a “point of no return” in the destruction of the islets, rendering some interventions effective only at the earlier stages of the process.
Among several approaches to prevention of T1D, “vaccination” using islet autoantigens (intact or altered peptides derived from insulin, GAD65 or other proteins) stands out as potentially inducing long-term tolerance by induction of regulatory T cells that down-regulate immunity to autoantigens. Until recently, trials of insulin administered parenterally, orally, or intranasally have been unsuccessful. Therefore, the initial results from trials of the Diamyd vaccine, as reviewed here, were greeted with huge interest and excitement. The vaccine includes the whole recombinant human GAD65 (rhGAD65) molecule suspended in alum. The protective effect was most pronounced in patients treated within 3 months of diagnosis, and no serious side effects were observed.
Insulin-related molecules continue to attract great interest in vaccine development. Phase I studies have been completed or are nearing completion for a proinsulin peptide C19-A3, an insulin peptide with incomplete Freund adjuvant, and a plasmid encoding proinsulin.
Combination therapies may enhance efficacy while lowering risk of adverse events if utilizing therapies from different treatment pathways. While more targeted therapies are being employed, immunomodulatory agents are still relatively nonspecific and potentially toxic to some of the trial participants.
In the long run, primary prevention will likely be the optimal approach to the prevention of T1D. Once more than one islet autoantibody is present, most individuals progress to diabetes in 5-10 years. The TrialNet consortium (
MARIAN REWERS, M.D., PH.D., is professor of pediatrics and preventive medicine at the Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver. He is on an advisory board for GlaxoSmithKline and provided medical-legal consultation for AstraZeneca.
