diapep-277 and Diabetes-Mellitus--Type-1

Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic β-cells. Current T1D therapies are exclusively focused on regulating glycemia rather than the underlying immune response. A handful of trials have sought to alter the clinical course of T1D using various broad immune-suppressors, e.g., cyclosporine A and azathioprine.(1-3) The effect on β-cell preservation was significant, however, these therapies were associated with unacceptable side-effects. In contrast, more recent immunomodulators, such as anti-CD3 and antigenic therapies such as DiaPep277, provide a more targeted immunomodulation and have been generally well-tolerated and safe; however, as a monotherapy there appear to be limitations in terms of therapeutic benefit. Therefore, we argue that this new generation of immune-modifying agents will likely work best as part of a combination therapy. This review will summarize current immune-modulating therapies under investigation and discuss how to move the field of immunotherapy in T1D forward.

Topics: CD3 Complex; Chaperonin 60; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Humans; Immunologic Factors; Insulin; Peptide Fragments; Treatment Outcome

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.

Topics: Antibodies, Monoclonal; Autoantigens; CD3 Complex; Chaperonin 60; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Immune Tolerance; Insulin; Insulin-Secreting Cells; Peptide Fragments; Protein Precursors; T-Lymphocytes

Regulatory T cells (Tregs) are responsible for the maintenance of peripheral tolerance. Animal studies have shown that administration of Tregs can prevent type 1 diabetes (DM1). Several clinical trials attempted to induce Tregs with various agents, and thus provide long-term tolerance of β cells in DM1. Nevertheless, most of these studies have focused on clinical parameters (e.g. C-peptide) and not Treg numbers nor their function after treatment. Therefore, it is not possible to conclude if the majority of these therapies failed because the drugs did not induce Tregs, or if they failed despite Treg expansion. The current knowledge regarding Tregs, along with our experience in Treg therapy of patients with graft versus host disease, prompted us to use ex vivo expanded Tregs in 10 children with recent-onset DM1. No adverse effects in the treated individuals were observed. There was a significant increase in Treg number in peripheral blood immediately after the treatment administration, while the first clinical differences between treated and control patients were observed 4 months after Treg injection. Treated individuals had higher C-peptide levels and lower insulin requirements than non-treated children. Eleven months after diagnosis of DM1, there are still 2 individuals who are independent of exogenous insulin. These results indicate that autologous Tregs are a safe and well-tolerated therapy in children with DM1, which can inhibit or delay the destruction of pancreatic β cells. Additionally, Tregs can be a useful tool for local protection of transplanted pancreatic islets. Isolation and expansion of antigen-specific Tregs is one of the directions for future studies on cellular therapy of DM1.

Topics: Adult; C-Peptide; Cell- and Tissue-Based Therapy; Chaperonin 60; Child; Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Interleukin-2; Peptide Fragments; Sirolimus; T-Lymphocytes, Regulatory

Type 1 diabetes is a chronic immune-mediated disease resulting in destruction of insulin-producing β-cells. Several studies have been performed aiming to halt disease progression after diagnosis; to reduce the increased diabetes risk in islet-autoantibody positive subjects; and to prevent the onset of β-cell autoimmunity in subjects genetically at risk but without autoantibodies. Whereas secondary prevention trials failed, trials in newly diagnosed patients have shown partial success in preserving C-peptide. These studies target T-cells and inflammation and make use of antigen-specific immune modulation or stem cell approaches. However, thus far no immune-based therapeutic regimen has cured type 1 diabetes after its clinical onset or has stabilized the decline of C-peptide to achieve the status of an approved drug. This review summarizes immune intervention trials and the current knowledge of DiaPep277® peptide as a form of immune intervention in type 1 diabetes.

Topics: Autoantibodies; Autoimmunity; C-Peptide; Chaperonin 60; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Immunotherapy; Islets of Langerhans; Peptide Fragments; T-Lymphocytes; Treatment Outcome

Type 1 diabetes is an autoimmune disease that gradually destructs insulin-producing beta cells. Over the years, clinicians' knowledge regarding the immunopathogenesis of this disease has greatly increased. Immunotherapies that can change the course of immune-mediated destruction and preserve and possibly regenerate the pancreatic beta cells seem to be promising in preclinical trials but so far have been unsuccessful in human studies. This article reviews the important immune interventions for type 1 diabetes that have been tried so far targeting the different stages of disease development and provides an insight into what the future might hold.

Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antilymphocyte Serum; Azathioprine; Basiliximab; Chaperonin 60; Cyclosporine; Daclizumab; Diabetes Mellitus, Type 1; Diet; Etanercept; Exenatide; Fatty Acids, Unsaturated; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Immunoconjugates; Immunoglobulin G; Immunosuppressive Agents; Insulin; Interferon-alpha; Interleukin 1 Receptor Antagonist Protein; Islets of Langerhans Transplantation; Niacinamide; Peptide Fragments; Peptides; Primary Prevention; Pyrazines; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Rituximab; Secondary Prevention; Sitagliptin Phosphate; Tertiary Prevention; Triazoles; Venoms; Vitamin D; Vitamins

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β-cells. The aim of immune intervention is to arrest this autoimmune attack. DiaPep277, a major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective in the modulation of the immune response in recent onset T1D and is the main focus of this review in the context of other ongoing trials using different approaches.. The authors performed a literature search of Pubmed listed publications (from the last 10 years) and a website search of the company licensing DiaPep277. DiaPep277 has been investigated in Phase I - III trials in humans. Phase II trials showed a significant preservation of β-cell function in adult T1D patients (but not children) with an absence of adverse effects and not accompanied by lower glycosylated haemoglobin (HbA1c) levels or reduced daily insulin requirement compared with placebo-treated patients.. Administration of DiaPep277 is safe and represents a promising therapeutic strategy in patients with recent-onset T1D. The results of two large Phase III trials will tell us whether this therapy may change our current approach to treating T1D patients at diagnosis.

Topics: Animals; Chaperonin 60; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Peptide Fragments

In type 1 diabetes, beta cells are attacked and destroyed by auto reactive T cells causing major impairment of blood glucose metabolism and, ultimately, the development of life-threatening complications. Currently, the treatment of this chronic disease is based on the use of endogenous insulin and no curative therapies are available. Treatment approaches in this respect need to be directed toward the primary causes of the disease tackling beta cells' auto reactive T cells. The goal of any curative intervention in type 1 diabetes is the preservation of insulin-secreting cells. This may be achieved by the abrogation of the pathogenic reactivity to beta cell auto antigens while preserving full capacity to generate a normal immune response against foreign antigens. In this review, some of the most promising drugs for immune intervention in type 1 diabetes are presented and discussed including phase 3 clinical trials that involve: DiaPep277, Anti-CD3 Otelixizumab, Glutamic Acid Decarboxylase (GAD) and anti-IL1 receptor antagonist. These approaches are currently being tested in international multicenter trials and all of them have a very similar outcome in terms of a beneficial effect on beta cells.

Topics: Animals; Blood Glucose; CD3 Complex; Chaperonin 60; Diabetes Mellitus, Type 1; Drug Design; Glutamate Decarboxylase; Humans; Immunologic Factors; Insulin-Secreting Cells; Peptide Fragments; Receptors, Interleukin-1; T-Lymphocytes

Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review.. A literature search of Pubmed listed publications covering 1990 - 2009 and a website search of the licensing company were performed.. DiaPep277 has been successfully employed in animal models and has been investigated in Phase I - III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes.. Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.

Topics: Animals; Chaperonin 60; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 1; Humans; Immunity, Innate; Immunologic Factors; Insulin-Secreting Cells; Peptide Fragments; T-Lymphocytes; Vaccination

In type 1 diabetes mellitus, autoimmune T-cells mount an attack on insulin producing beta-cells eventually causing hyperglycemia. It is hypothesized, that to prevent and treat this disease, one must interfere with the autoimmune process. To avoid hazardous side effects, this intervention should not cause a global immune suppression but immune modulation. DiaPep277 (peptide 277) is a 24 amino acid peptide derived from positions 437-460 in HSP60. It has recently been shown to have an immune modulatory effect on diabetogenic T cells in animal models of diabetes. It has also been recently implicated as a possible auto-antigen in type 1 diabetes. Promising results in animal models led to phase 1 to 3 human clinical trials in patients with type 1 diabetes, the results of which are the focus of this review. A combined analysis of all the adult phase II studies revealed that DiaPep277 significantly inhibits the decline in stimulated C-peptide secretion (thus preserving endogenous insulin secretion). This effect was more pronounced in patients with a high beta-cell reserve at the start of the treatment. Furthermore, opposite trends in glycemic control of DiaPep277 treated patients where noted as opposed to placebo treated patients. The phase III study has began more than 2 years ago in 40 medical centers worldwide, and thus far recruited over 350 patients around the world. If DiaPep277 will prove to be efficacious, it will cause a paradigm shift in the treatment of type 1 diabetes, from treating the subsequent insulin deficiency to addressing the initial autoimmune process that is at the heart of the disease.

Topics: Animals; Blood Glucose; C-Peptide; Chaperonin 60; Diabetes Mellitus, Type 1; Humans; Immunologic Factors; Insulin; Insulin Secretion; Insulin-Secreting Cells; Peptide Fragments; Peptides; T-Lymphocytes

Topics: Chaperonin 60; Diabetes Mellitus, Type 1; Humans; Immunologic Factors; Immunotherapy; Insulin-Secreting Cells; Peptide Fragments; Peptides

DiaPep277, a 24-amino acid peptide based on residues 437 to 460 of heat shock protein 60, is undergoing phase II clinical trials by DeveloGen for the potential treatment and prevention of established and newly diagnosed type 1 diabetes symptoms of the prediabetic state and of latent autoimmune diabetes of the adult.

Topics: Animals; Chaperonin 60; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 1; Drug Industry; Humans; Hypoglycemic Agents; Peptide Fragments; Peptides; Structure-Activity Relationship; Treatment Outcome

Topics: Adjuvants, Immunologic; Animals; Biguanides; Chaperonin 60; Diabetes Mellitus, Type 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Niacinamide; Peptide Fragments; Peptides; Regeneration; Sulfonylurea Compounds; Thiazoles

Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes.. A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC).. The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose.. Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

Topics: Adolescent; Adult; Area Under Curve; Blood Glucose; C-Peptide; Chaperonin 60; Diabetes Mellitus, Type 1; Double-Blind Method; Fasting; Female; Food; Gastrointestinal Agents; Glucagon; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Meals; Middle Aged; Peptide Fragments; Young Adult

To investigate whether lower risk HLA class II genotypes would influence the efficacy of DiaPep277 therapy in protecting β-cell function evaluated by C-peptide secretion in recent-onset type 1 diabetic subjects.. Data were collected from type 1 diabetic subjects enrolled in multicenter phase II studies with a randomized, double-blind, and placebo-controlled design in whom fasting and stimulated C-peptide levels were measured. HLA genotypes were classified in high, moderate, and low risk categories.. A total of 146 subjects (aged 4.3 to 58.5 years) were enrolled, including 76 children (<18 years old) and 70 adults. At baseline, there was a significant increase in fasting, maximal, and area under the curve (AUC) C-peptide from high to moderate and low risk HLA genotypes in adults (P for trend <0.04) but not in children. Children showed a decrease of the three parameters over time regardless of therapy and HLA genotype. DiaPep277-treated adults with low risk genotype had significantly higher maximal and AUC C-peptide versus placebo at 12 months (0.04 ± 0.07 vs. -0.28 ± 0.09 nmol/L, P < 0.01, and 0.53 ± 1.3 vs. -4.59 ± 1.5 nmol/L, P < 0.05, respectively). In the moderate risk genotype group, Δmaximal and AUC C-peptide values were significantly higher in DiaPep277-treated versus placebo-treated patients (P < 0.01 and P < 0.05, respectively).. This exploratory study demonstrates that type 1 diabetic adults with low and moderate risk HLA genotypes benefit the most from intervention with DiaPep277; the only subgroup with an increase of C-peptide at 12 months after diagnosis was the low risk DiaPep277-treated subgroup.

Topics: Adolescent; Adult; Age Factors; C-Peptide; Chaperonin 60; Child; Child, Preschool; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Genes, MHC Class II; Genetic Association Studies; Humans; Hypoglycemic Agents; Immunologic Factors; Insulin-Secreting Cells; Kinetics; Male; Middle Aged; Peptide Fragments; Young Adult

An immunogenic peptide (p277) from the 60-kDa heat shock protein (hsp60) arrested beta-cell destruction in non-obese diabetic mice. A randomized, double-blind, phase Ib/II clinical trial of DiaPep277 peptide treatment was performed in recent-onset type 1 diabetes patients with remaining insulin production. We studied the immunological efficacy of this peptide therapy and correlated this with clinical outcome. Forty-eight C-peptide-positive patients were assigned subcutaneous injections of 0.2, 1.0 or 2.5 mg p277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). T cell autoimmunity to hsp60, DiaPep277, glutamic acid decarboxylase and tetanus toxoid (recall response control) were assayed by proliferation and cytokine secretion assays (enzyme-linked immunospot) at regular intervals until 18 months after the first injection. All treated patients at each dosage of peptide demonstrated an altered immune response to DiaPep277, while the majority of placebo-treated patients remained non-responsive to treatment (P = 0.00001), indicating a 100% efficacy of immunization. Cytokine production in response to therapy was dominated by interleukin (IL)-10. IL-10 production before therapy and decreasing autoantigen-specific T cell proliferation were associated with beta-cell preservation. Third-party control immune responses were unaffected by therapy. No potentially adverse immunological side effects were noted. DiaPep277 is immunogenic in type 1 diabetic subjects and has immune modulating properties. Immunological monitoring distinguished therapy from placebo treatment and could determine immunological efficacy. Declining or temporary proliferative responses to peptide DiaPep277 treatment may serve as an immunological biomarker for clinical efficacy.

Topics: Cell Proliferation; Chaperonin 60; Cytokines; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Double-Blind Method; Glutamate Decarboxylase; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Lymphocyte Activation; Peptide Fragments; Peptides; T-Lymphocytes; Tetanus Toxoid; Treatment Outcome

Type 1 diabetes results from a T-cell mediated autoimmune destruction of insulin-producing pancreatic beta-cells. The 60-kDa heat-shock protein (hsp60) is one of the known target self-antigens. An immunogenic peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic non-obese diabetic (NOD) mice. A randomized, double-blind, phase Ib/II study of peptide treatment was undertaken in recent onset type 1 diabetes patients with remaining insulin production.. Forty-eight recent onset type 1 diabetes patients were assigned subcutaneous injections of 0.2, 1.0 or 2.5 mg peptide DiaPep277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). The primary clinical endpoints were safety and efficacy (glucagon-stimulated C-peptide production at 6 and 12 months); secondary endpoints were HbA1c levels and daily insulin dose adjusted for body weight at 2, 6, 12 and 18 months.. C-peptide levels decreased over time in all groups except the 2.5 mg-treated. The decrease in C-peptide production was less in treated patients versus placebo, mostly in the 2.5 mg group. HbA1c increased significantly in the 1.0 mg group and in the 2.5 mg group at 2 and 18 months, respectively. No differences were seen in daily insulin doses. One patient was withdrawn from the study possibly owing to a treatment-related adverse event.. Multiple DiaPep277 peptide administration seems safe and may have a beneficial effect on C-peptide levels over time, but this finding is not supported by lower HbA1c levels or daily insulin requirement. Further investigation on a larger scale is warranted.

Topics: C-Peptide; Chaperonin 60; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunologic Factors; Insulin; Peptide Fragments; Peptides; Time Factors; Treatment Outcome

Aim of this trial was to test whether heat shock protein peptide DiaPep277 treatment in adult and paediatric patients with recent-onset type 1 diabetes (T1D) is safe and whether it can preserve endogenous insulin production.. Two studies were performed in a prospective, multicentre, double-blind, placebo-controlled trial. Fifty adult (study p520, aged 16-44 years) and 49 paediatric patients (study p521, 4-15 years) with recent-onset T1D were treated subcutaneously at four different time points with 0.2 mg or 1.0 mg DiaPep277 versus placebo and followed for 18 months. Adult patients were treated with 0.2 mg, 1.0 mg or 2.5 mg DiaPep277 versus placebo. Stimulated C-peptide served as readout for functional beta-cell-mass.. DiaPep277-treatment was not associated with severe side effects. No differences were found in placebo and DiaPep277 treated groups. In adults, a modest trend towards better maintenance of beta-cell function was observed in the 0.2 mg and 1.0 mg group, while there was significant loss of stimulated C-peptide in the placebo and 2.5 mg group. Paediatric patients with low HLA risk showed stable C-peptide levels until 13 months upon treatment with 1 mg DiaPep277. Despite similar stimulated C-peptide levels at baseline, children exhibited a more pronounced loss of beta-cell function over 18 months than adults (p = 0.0003).. Administration of DiaPep277 seems safe and may have beneficial effects on C-peptide levels over time in some patients with T1D, but this finding was not accompanied by reduced HbA1c or insulin requirement. Studies with more patients and longer follow-up are needed to further study the effect of DiaPep277.

Topics: Adolescent; Adult; Autoantibodies; C-Peptide; Chaperonin 60; Child; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; HLA Antigens; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Peptide Fragments; Peptides

Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements.. Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints.. At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred.. Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

Topics: Adolescent; Adult; C-Peptide; Chaperonin 60; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Peptide Fragments; Peptides

Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that leads to the destruction of insulin-producing beta cells. Treatment with DiaPep277, a peptide derived from heat-shock protein 60 (hsp60), has been found to slow the deterioration of beta-cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta-cell destruction in children with recent-onset T1DM.. A prospective, randomized, double-blind, phase II design was used. The sample included 30 children (19 males) aged 7-14 years who had been diagnosed with T1DM from 53 to 116 days previously, and had basal C-peptide concentrations above 0.1 nmol/L. The children were randomized to receive subcutaneous injections of 1 mg DiaPep277 (15 patients) or 40 mg mannitol (placebo) at entry and at 1, 6, and 12 months. The duration of follow-up was 18 months. The groups were compared for stimulated C-peptide level, exogenous insulin dose, and HbA1c concentration.. C-peptide levels similarly decreased over time in the DiaPep277- and placebo-treated patients. There was no significant difference in insulin dose or HbA1c concentration between the groups at any time point. No serious drug-related adverse effects were recorded throughout the study period.. One-year treatment with DiaPep277 at a dosage of 1 mg is safe for use and well tolerated in children with recent-onset T1DM. However, it appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.

Topics: Adolescent; C-Peptide; Chaperonin 60; Child; Child, Preschool; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Gastroenteritis; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Male; Peptide Fragments; Peptides; Treatment Outcome

DiaPep277 is an immunomodulatory peptide that arrests beta cell destruction in mouse models of type 1 diabetes mellitus (T1DM). This article extends an original pilot observation to two studies of 61 patients (age > 16 years), diagnosed with T1DM within 6 months, and with measurable beta cell function. Patients were treated with placebo (n = 27) or 1.0 mg DiaPep277 (n = 34). After 13 months, 1.0 mg Dia Pep277 treatment significantly (P = 0.02) preserved beta cell function as compared to the control with a trend for reduced HbA1c. This was achieved without an increase in insulin dose in the DiaPep277 group and with excellent safety. DiaPep277-treated patients also had fewer Th1 DiaPep277-specific T cells.

Topics: Amino Acid Sequence; Area Under Curve; C-Peptide; Chaperonin 60; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Molecular Sequence Data; Peptide Fragments; Peptides; Time Factors; Treatment Outcome

Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize-potentially even reverse-the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.

Topics: Alum Compounds; Animals; Antibodies, Monoclonal, Humanized; Antigens; Antilymphocyte Serum; BCG Vaccine; Chaperonin 60; Diabetes Mellitus, Type 1; Forecasting; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Interleukin-2; Mice; Peptide Fragments; Pilot Projects; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Abatacept; Antibodies, Monoclonal, Humanized; Autoantigens; CD3 Complex; Chaperonin 60; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Glutamate Decarboxylase; Humans; Immunoconjugates; Immunotherapy; Peptide Fragments; Recombinant Fusion Proteins

Environmental factors such as diet and bacterial antigens play an important role in the onset of Type 1 diabetes. Different self-antigens are suggested to play a role in the development of diabetes. Antibodies against the 60-kDa heat shock protein 60, which have a high homology to bacterial heat shock protein 65, have been found in the circulation at the onset of diabetes in humans and in pre-diabetic NOD-mice. One of the immunodominant epitopes in autoimmune diabetes is p277, a specific peptide of human heat shock protein 60 corresponding to positions 437-460. In this study we investigated whether neonatal oral administration of DiaPep277 (a synthetic peptide analogue of p277) affected the development of diabetes in the BioBreeding-Diabetes Prone (BB-DP) rat, and whether this could potentiate the effect of a protective hydrolysed casein-diet.. BB-DP rats were orally inoculated once per day with placebo or DiaPep277 at days 4, 5, 6 and 7 of life. At the age of 21 days rats were weaned on to a conventional, cereal-based diet or on to the hydrolysed casein-diet.. The development of diabetes in animals receiving DiaPep277 in combination with the hydrolysed casein-diet was delayed by 17 days, and a relative reduction of the incidence by 64% was seen. Non-diabetic animals did not show any sign of insulitis.. Short-term neonatal feeding with p277 in early life, combined with diet adaptation, appears to provide a procedure to significantly reduce the development of Type 1 diabetes in later life.

Topics: Administration, Oral; Aging; Animals; Chaperonin 60; Diabetes Mellitus, Type 1; Humans; Mice; Mice, Inbred NOD; Peptide Fragments; Peptides; Rats; Rats, Inbred BB

Topics: Adult; Animals; Antibodies, Monoclonal; CD3 Complex; Chaperonin 60; Child; Child, Preschool; Diabetes Mellitus, Type 1; Genetic Markers; Genetic Predisposition to Disease; Humans; Infant, Newborn; Mice; Peptide Fragments; Peptides; Primary Prevention; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Member 25

Topics: Adjuvants, Immunologic; Animals; C-Peptide; Chaperonin 60; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Humans; Peptide Fragments; Peptides