Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes

Agardh, Carl‐David; Cilio, Corrado; Lethagen, ÅsaLinda; Lynch, Kristian; Leslie, R. D. G.; Palmér, Mats; Harris, Robert A.; Robertson, John A.; Lernmark, Åke

doi:10.1016/j.jdiacomp.2004.12.003

Cited by 206 publications

(157 citation statements)

References 23 publications

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“…This is clearly worthy of an international multicentre effort to compare early insulin therapy with conventional oral treatment strategies on their relative beta cell sparing effects and long-term outcome of the disease. Moreover, LADA is considered our best prospect for assessment of tolerogenic immunotherapy [19].…”

mentioning

confidence: 99%

Latent autoimmune diabetes in adults (LADA)—more than a name

et al. 2006

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mentioning

confidence: 99%

Latent autoimmune diabetes in adults (LADA)—more than a name

et al. 2006

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“…While insulin autoimmunity is affecting the young, GAD65 autoimmunity is less sensitive to age. Alum-formulated recombinant human GAD65 tested in Phase II and III clinical trials were found to be safe [38][39][40] . The immunomodulating effect seemed to include the induction of Treg cells 16,38 and the residual beta-cell function in newly diagnosed T1D patients.…”

Section: Glutamic Acid Decarboxylase (Gad65)mentioning

confidence: 99%

“…Alum-formulated recombinant human GAD65 tested in Phase II and III clinical trials were found to be safe [38][39][40] . The immunomodulating effect seemed to include the induction of Treg cells 16,38 and the residual beta-cell function in newly diagnosed T1D patients. We have randomized a total of 50 children in the trial Diabetes Prevention -Immune Tolerance (DIAPREV-IT) to either placebo or alum-formulated GAD65 in a prime and boost design (NCT01122446).…”

Section: Glutamic Acid Decarboxylase (Gad65)mentioning

confidence: 99%

“…Similar failure to affect the c-peptide disappearance rate over 15 months follow-up was found in a phase III study (NCT00723411) carried out in Europe 54 . The lack of effects of the GAD65-alum approach has complicated further clinical investigations especially as the possible effects of the treatment on immune parameters such as the induction of Treg cells 38,55 are still to be reported.…”

Section: Gad-alummentioning

confidence: 99%

“…Whether a future trial is prevention or intervention safety and long-term effects will have to be a major concern. So far, the safety profile in trials with insulin 22,36 and GAD65 38,40 autoantigen immunomodulation has been high. The different approaches of autoantigen administration have revealed effects on secondary end-point measures such as increased numbers of Treg cells.…”

Section: E Future Directionsmentioning

confidence: 99%

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Immune therapy in type 1 diabetes mellitus

Lernmark

Larsson

2013

Nat Rev Endocrinol

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(200 words) Type 1 diabetes mellitus (T1D) is an autoimmune disorder directed against the pancreatic islet β cells. The genetic risk for the disease is linked to HLA-DQ genotypes and unknown environmental triggers. In most countries, only 10-15% of newly diagnosed T1D children or young adults have a first degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may develop already at 1-2 years of age. Immune therapy in T1D is approached at three stages. Primary prevention is treatment of subjects at increased genetic risk. The TRIGR trial is testing if hydrolyzed casein milk formula may reduce T1D in genetically predisposed infants. Secondary prevention is in subjects with persistent islet autoantibodies. On-going trials are either non-autoantigen (BCG, CD3 monoclonal antibodies) or autoantigen (oral and nasal insulin or Alum-formulated GAD65) specific. Intervention at diabetes onset include non-autoantigen (CD3 monoclonal antibodies, IL-2 receptor antibodies, Il-1b receptor inhibitor, Il-1b antibodies, BCG, ATG, DiaPep277) and autoantigen (proinsulin peptides) specific therapy. Although preserved beta-cell function long term has been difficult to achieve in many prior studies, considerable progress is being made through controlled clinical trials and animal investigations to uncover mechanisms of beta-cell destruction. Novel therapies that would prevent islet autoimmunity or halt progressive beta-cell destruction need to be designed.

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