A 1-year pilot study of intralymphatic injections of GAD-alum in individuals with latent autoimmune diabetes in adults (LADA) with signs of high immunity: No safety concerns and resemblance to juvenile type 1 diabetes.

AIMS: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. MATERIALS AND METHODS: Three GAD-alum injections, 4 µg each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. RESULTS: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). CONCLUSION: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients.

Anti-glutamic Acid Decarboxylase Antibody-Positive Gestational Diabetes Mellitus with Autoimmune Type 1 Diabetes Mellitus in the Early Postpartum Period: A Case Report and Literature Review.

Gestational diabetes mellitus (GDM) is a state of pre-diabetic impaired glucose tolerance initially occurring during pregnancy. Although abnormalities in glucose metabolism normally resolve rapidly after delivery, women with GDM have a higher lifetime risk of developing diabetes mellitus than those without GDM; thus, postpartum healthcare is essential. Of all GDM patients, 5%-10% test positive for diabetes-related autoantibodies, which increase the risk of developing type 1 diabetes mellitus (T1DM). Autoantibody measurement in GDM screening remains debatable; however, it may be useful for the postnatal follow-up of GDM patients at high risk of developing T1DM. We treated a 29-year-old woman who was GDM positive for anti-glutamic acid decarboxylase antibody (GADA) requiring high-dose insulin therapy during pregnancy. As the patient tested positive for GADA, she received judicious postpartum management, allowing for early diagnosis of T1DM and resumption of treatment. Her insulin secretory capacity was preserved at 1 year after parturition, suggesting either slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults. This was a rare case of slowly progressive insulin-dependent T1DM or latent autoimmune diabetes in adults in the early postpartum period, but the fact that GADA was positive during pregnancy enabled early treatment without overlooking it. Measuring diabetes-related autoantibodies in patients considered to be at a high risk for T1DM, such as those who are of slim build, young, or suffering from autoimmune thyroid disorders, may be important for appropriate individualized follow-up.

Baseline Characteristics and Predictive Factors of Intravenous Immunoglobulin Response in Drug and Device Refractory Gastroparesis Symptoms.

INTRODUCTION: Intravenous immunoglobulin (IVIG) has been shown in a small pilot series to be helpful for some patients with gastroparesis that is refractory to drugs, devices, and surgical therapies. Many but not all patients have serologic neuromuscular markers. We hypothesize that those patients with serologic markers and/or longer duration of therapy would have better responses to IVIG. MATERIALS AND METHODS: We studied 47 patients with a diagnosis of gastroparesis and gastroparesis-like syndrome that had all failed previous therapies including available and investigational drugs, devices, and/or pyloric therapies. Patients had a standardized 12-week course of IVIG, dosed as 400 mg/kg per week intravenously. Symptom assessment was done with Food and Drug Administration (FDA) compliant traditional patient-reported outcomes. Success to IVIG was defined as 20% or greater reduction in average symptom scores from baseline to the latest evaluation. RESULTS: Fourteen patients (30%) had a response, and 33 (70%) had no response per our definition. Patients responding had a higher glutamic acid decarboxylase 65 positivity (64% vs. 30%, P =0.049, missing=3) and longer duration of therapy (>12 wk/continuous: 86% vs. 48%, P =0.09). CONCLUSIONS: In this moderately sized open-label series of refractory patients with gastroparesis symptoms treated with IVIG, 30% of patients responded. While serologic markers and extended therapies show a trend to greater response, neither was statistically significant, except for glutamic acid decarboxylase 65 which showed a higher positivity rate in responders. We conclude that a clinical trial of IVIG may be warranted in severely refractory patients with gastroparesis symptoms.

Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D.

Background: Latent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study). Material and Methods: Fourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 µg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed. Results: Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months). Conclusions: Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.

Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats.

Schizophrenia is a common mental disorder affecting patients' thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 µg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.

Glutamic acid decarboxylase immunotherapy for type 1 diabetes.

PURPOSE OF REVIEW: To describe recent development of an autoantigen (GAD) treatment towards well tolerated and efficacious precision medicine in type 1 diabetes. RECENT FINDINGS: Although subcutaneous GAD-alum treatment failed to reach primary endpoint in a phase III trial, metanalyses showed a 97% probability of efficacy, and clear efficacy in patients carrying Hyman Leucoycte Antigen (HLA) DR3DQ2. Efforts have been made to improve efficacy by trying combination therapies with vitamin D + Ibuprofen resp vitamin D + Etanercept (TNF-α inhibition), without any breakthrough until the administration of GAD-alum was changed from subcutaneous to intralymphatic. With a very small dose of GAD-alum (4 µg) given into an inguinal lymph three times with 1 month interval, the efficacy in patients with HLADR3DQ2 has been impressive, with significantly better beta cell preservation than patients who got placebo in a double-blind randomized trial, and clinical efficacy with more patients in partial remission (IDAA1c < 9) and larger proportion of patients with CGM-measured blood glucose Time In Range (TIR), significantly correlated to the C-peptide values. The treatment has been easy for patients and healthcare without treatment-related risk or adverse events. SUMMARY: Intralymphatic GAD-alum treatment in type 1 diabetes patients carrying HLA DR3DQ2 seems to be an attractive immune intervention.

GAD65 Autoimmune Encephalitis: A Cause of Rapidly Evolving Frontotemporal Atrophy.

We describe a patient who presented with subacute onset of short-memory impairment, disorientation, and gait instability, with progressive deterioration. Workup demonstrated glutamic acid decarboxylase antibody-related encephalitis. Aggressive immunotherapy with high-dose intravenous corticoids, followed by slow oral taper, plasmapheresis, rituximab, and cyclophosphamide did not halt disease progression. During follow-up, she developed a frontotemporal dementia phenotype. Serial imaging showed the appearance of marked atrophy of the frontal and anterior temporal regions. We conclude that glutamic acid decarboxylase antibody-related encephalitis may rarely present with a treatment-refractory frontotemporal phenotype.

Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes.

AIM: We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. MATERIAL AND METHODS: Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 µg, Diamyd™) Day 30 and 60. They were followed for 30 months. RESULTS: No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. CONCLUSIONS: Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.

Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine if retention of C-peptide following immunotherapy using recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum) is influenced by HLA risk haplotypes DR3-DQ2 and DR4-DQ8. METHODS: HLA-dependent treatment effect of GAD-alum therapy on C-peptide retention in individuals with recent-onset type 1 diabetes was evaluated using individual-level patient data from three placebo-controlled, randomised clinical trials using a mixed repeated measures model. RESULTS: A significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3-DQ2 but not HLA-DR4-DQ8 and in the broader subgroup of individuals positive for all genotypes that include HLA-DR3-DQ2 (i.e. including those also positive for HLA-DR4-DQ8). Higher doses (three or four injections) showed a treatment effect ratio of 1.596 (95% CI 1.132, 2.249; adjusted p = 0.0035) and 1.441 (95% CI 1.188, 1.749; adjusted p = 0.0007) vs placebo for the two respective HLA subgroups. CONCLUSIONS/INTERPRETATION: GAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype. Graphical abstract.

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route.

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology.

BACKGROUND: Evidence suggests that GABA may reduce pancreatic inflammation, protect ß-cells from autoimmune destruction, and potentiate the regeneration of new ß-cells in the setting of type 1 diabetes mellitus (T1DM). The enzyme GAD, also expressed in human pancreatic ß-cells, is an antigenic target of reactive T cells. We hypothesized that treatment of children with recent onset T1DM with GABA or combination GABA with GAD will preserve ß-cell function and ameliorate autoimmune dysregulation. METHODS: This is a one-year, prospective, randomized, double-blind, placebo-controlled trial. Ninety-nine patients aged 4-18 years with newly diagnosed T1DM are randomized into three treatment groups: 1) oral GABA twice daily in addition to two injections of recombinant GAD enzyme, 2) oral GABA plus placebo GAD injections, or 3) placebo GABA and placebo GAD. Patients are evaluated at baseline and months 1, 5, 8 and 12. Mixed meal tolerance testing is performed at all but the 8-month visit. Laboratory studies will assess indices of beta and alpha cell function, glycemic control, immunophenotyping, and diabetes-related autoantibodies. RESULTS: The primary outcome is the effect on pancreatic ß-cell function as measured by meal-stimulated c-peptide secretion compared between the treatment groups before and after one year of treatment. Secondary outcomes include: 1) fasting and meal stimulated glucagon and proinsulin levels, 2) response in insulin usage by participants, 3) indices of immune cell function, and 4) effect on autoantibodies GAD65, ICA512, and ZnT8. CONCLUSIONS: This trial will determine the safety and efficacy of GABA and combination GABA/GAD therapy to delay T1DM progression in children.

Treatment of Latent Autoimmune Diabetes in Adults: What is Best?

Latent Autoimmune Diabetes in Adults (LADA), although formally classified as Type 1 Diabetes (T1D), very often (at least in Western countries) appear clinically with Type 2 Diabetes (T2D)-like features as overweight and insulin resistance. LADA patients do not need exogenous insulin at the time they are diagnosed with diabetes, but a large percentage will within a few years develop need for such treatment. The decline in beta cell function progresses much faster in LADA than in T2D, presumably because of the ongoing autoimmune assault in LADA, and therefore necessitates insulin therapy much earlier in LADA than in T2D. Despite high prevalence of LADA (about 10% of the total diabetic population in many countries), the treatment of LADA patients is far less elucidated than is the case for T1D and T2D. Finding a treatment strategy for LADA from the time of diagnosis, that can reduce the decline of beta cell function, ensure adequate metabolic control and thereby reduce the risk of diabetic complications is thus an important clinical challenge. Conclusions from the randomized treatment studies so far do not indicate an optimal treatment strategy in LADA. This review aims to give an overview of current practices for the medical treatment of LADA as well as an update on results from recent studies on the treatment of the disease.

Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial.

OBJECTIVE: Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen-specific treatment with alum-formulated glutamate decarboxylase (GAD-Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmunity. METHODS: In an investigator-initiated, double-blind, placebo-controlled clinical trial, non-diabetic children aged 4 to 17.9 years with autoantibodies to glutamate decarboxylase (GADA) and at least one of insulinoma-associated protein 2, insulin or zinc-transporter 8, were randomized, stratified by 2 or ≥3 islet autoantibodies, to 2 injections of 20 µg GAD-Alum or placebo, 30 days apart. Main outcome was safety, investigated by adverse events, hematology, chemistry, thyroid and celiac autoimmunity and titers of islet autoantibodies, and efficacy, investigated by cumulative incidence of diabetes onset over 5-year follow-up. Secondary variables: change in first-phase insulin release (FPIR) after intravenous glucose tolerance tests, fasting, 120 minutes and Area under the curve (AUC) C-peptide and p-glucose after oral glucose tolerance tests and HbA1c. RESULTS: Fifty children (median age: 5.2) were assigned 1:1 to GAD-Alum or placebo, all receiving full treatment and included in the analyses. GAD-Alum did not affect any safety parameter, while GADA titers increased (P = .001). Time to clinical diagnosis was not affected by treatment (hazard ratio, HR = 0.77, P = .574) in the full population or in the separate stratum groups. Treatment did not affect any of the secondary variables. CONCLUSIONS: GAD-Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD-Alum should prove useful in future prevention studies.

A Swedish approach to the prevention of type 1 diabetes.

BACKGROUND: The autoimmune destruction of beta cells, resulting in clinical type 1 diabetes, may start early in life and last for several months or years. During this period of time, we have an opportunity to try to prevent or delay further beta-cell destruction and clinical onset of type 1 diabetes. OBJECTIVES: Ongoing prediction and prevention studies in Skåne, Sweden are described. METHODS: During September 2000 to August 2004, 35 000 children were screened at birth for genetic type 1 diabetes risk in the Diabetes Prediction in Skåne Study (DiPiS). In August 2004, the screening continued within the Enviromnental Determinants of Diabetes in the Young study (TEDDY). In the clinical trial Diabetes Prevention - Immune Tolerance (DiAPREV-IT), children with multiple islet autoimmunity have been included to investigate if immune tolerance with Alum-formulated GAD65 may prevent further beta-cell loss. RESULTS: In DiPiS and TEDDY, a large number of children are followed in order to find the factors that trigger the autoimmune process leading to type 1 diabetes. Children followed in the studies develop diabetes at an early stage of disease, with few symptoms and a low frequency of diabetes ketoacidosis. DiAPREV-IT is still blinded and results will be available in December 2016. CONCLUSION: Large prospective studies will be needed to understand the complex process leading to type 1 diabetes. Secondary prevention may be possible in children with islet autoimmunity, but the studies are complicated by the variability of glucose metabolism and beta-cell loss.

GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months.

BACKGROUND: This study aimed to analyse data from two different studies (phase II and phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) at 30 months after administration to children and adolescents with type 1 diabetes. METHODS: The phase II trial was a double-blind, randomised placebo-controlled study, including 70 children and adolescents who were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and 1 month later. During a subsequent larger European phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up, and 45 patients completed the trial at 30 months. Both studies included GAD65 auto-antibodies-positive patients with fasting C-peptide ≥ 0.10 nmol/l. We have now combined the results of these two trials. RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide area under the curve had decreased significantly less (9 m: p < 0.037; 15 m: p < 0.032; 21 m: p < 0.003 and 30 m: p < 0.004), and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide > 0.2 nmol/L (p < 0.05), as compared with placebo. CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset type 1 diabetes shows no adverse events and preserves residual insulin secretion.

Prevention versus intervention of type 1 diabetes.

Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials.

Trials in type 1 diabetes: Antigen-specific therapies.

Type 1 diabetes (T1D) results from an aberrant immunological response against the insulin-producing beta cells in the islets of the pancreas. The ideal therapy would restore immune balance in a safe and lasting fashion, stopping the process of beta cell decay. The efficacy of immune suppressive agents such as cyclosporin underscores the notion that T1D can in principle be prevented, albeit at an unacceptable long-term safety risk. Immune modulatory drugs such as monoclonal anti-CD3 antibody, on the other hand, have recently had rather disappointing results in phase 3 trials, possibly due to inadequate dosing or choice of inappropriate endpoints. Therefore, it is argued that striking the right balance between safety and efficacy, together with careful trial design, will be paramount in preventing T1D. Here we outline the concept of antigen-specific tolerization as a strategy to safely induce long-term protection against T1D, focusing on available clinical trial data, key knowledge gaps and potential future directions.

Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals.

Previous studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff-person syndrome (SPS) patients. In a Phase II trial using aluminium-formulated GAD(65) (GAD-alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD-alum could induce GADA with SPS-associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1-4 subclass frequencies, b78- and b96·11-defined epitope distribution and GAD(65) enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD-alum-treated T1D patients (n = 9), T1D high-risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in-vitro GAD(65) enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78-defined epitope was found in the SPS group compared to T1D and GAD-alum individuals, whereas no differences were detected for the b96·11-defined epitope. GADA IgG1-4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in-vitro GADA phenotypes from SPS patients differed from the T1D- and high-risk groups, and GAD-alum treatment did not induce SPS-associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.

Primary and secondary prevention of Type 1 diabetes.

Since type 1 diabetes is an immunologically mediated disease, immune intervention should alter the natural history of the disease. This article reviews prevention studies undertaken either prior to any evidence of autoimmunity (primary prevention) or after the development of islet autoantibodies (secondary prevention). Most immune intervention studies have been conducted in recent-onset type 1 diabetes (tertiary prevention), and these are not reviewed herein. The goal of primary and secondary intervention is to arrest the immune process and thus prevent or delay clinical disease. Primary prevention studies have been conducted in infants with high genetic risk. Interventions tested include several dietary manipulations, including infant formulas free of either cow's milk or of bovine insulin, infant formula supplemented with the omega-3-fatty acid docosahexaenoic acid, delayed introduction of gluten-containing foods, and vitamin D supplementation. Secondary prevention studies have been conducted in both children and adults with diabetes autoantibodies. Interventions tested include nicotinamide, insulin injections, oral insulin, nasal insulin, glutamic acid decarboxylase, and cyclosporine. Underway are secondary prevention studies with teplizumab and with abatacept.

Recent progress in gene therapy for Parkinson's disease.

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD.