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February 16, 2018

Common Blood Pressure Drug Found to Prevent Type 1 Diabetes

Source: RapidEye/Getty Images

  • A drug that is commonly used to treat high blood pressure in children and adults could potentially help to prevent the onset of type 1 diabetes (T1D) in up to 60% of at-risk patients, according to U.S. researchers.

    A team led by Aaron Michels, M.D., at the University of Colorado Anschutz (CU Anschutz) Medical Campus, and colleagues at the University of Florida in Gainesville, tested methyldopa in a small number of patients with recent-onset T1D who also carried the DQ8 version of a major histocompatibility (MHC) protein. Results from the study found that methyldopa therapy reduced inflammatory insulin-specific T-cell responses, and indicated that the drug may also limit beta-cell destruction and preserve function.

    “This is the first personalized treatment for T1D prevention," comments Dr. Michels, who is a researcher at the Barbara Davis Center for Childhood Diabetes and associate professor of medicine at CU Anschutz. "With this drug, we can potentially prevent up to 60% of T1D in those at risk for the disease. This is very significant development."

    The researchers report their findings in the Journal of Clinical Investigation, in a paper entitled “Methyldopa Blocks MHC Class II Binding to Disease-Specific Antigens in Autoimmune Diabetes.” 
    T1D results from the chronic autoimmune-mediated destruction of insulin-producing beta-cells in the pancreatic islets, and while a number of immune therapies designed to slow or prevent beta-cell loss have been tested in clinical trials, “these therapies have shown limited clinical benefit to date,” the authors explain. 

    For many autoimmune disorders, human leukocyte antigen (HLA) complex genes are associated with increased risk. In T1D, the HLA-DQ8 allele is present in 50% to 60% of all patients, and “confers significant disease risk and is involved in disease pathogenesis.”

    The authors hypothesized that blocking DQ8 antigen presentation might prevent the recognition of self-peptides by pathogenic T cells and so help to prevent the development of T1D in patients. They used the crystal structure of DQ8 to screen for small molecules that might bind to specific pockets within the protein’s structure and inhibit DQ8 antigen presentation. Tests in cell cultures and in the nonobese diabetic (NOD) mouse model of T1D showed that the candidate tetraazatricyclododecane (TATD) delayed the onset of diabetes and prevented disease in half of the treated mice.

    Starting TATD therapy when NOD mice had already developed more established disease led to maintenance of normal blood glucose and preserved glucose tolerance. “Overall, these data indicate that therapeutic blocking of MHC II antigen presentation in a spontaneous model of autoimmune diabetes prevents disease onset, blocks critical interactions between T and B cells, lessens tissue-specific destruction and maintains glucose tolerance when administered in later stages of diabetes development,” the team writes.

    The researchers then screened 1207 FDA-approved small-molecule drugs that were predicted to occupy the same pocket as TATD “in an attempt to repurpose an existing drug.” The screen identified methyldopa, which has been used to treat high blood pressure for more than 50 years. The researchers first evaluated methyldopa in cultured cells, and then tested the drug in a DQ8 transgenic mouse model, which confirmed that administration blocks DQ8 antigen presentation. They then carried out an open-label clinical study in 20 human patients, aged 18–46 years, who carried the DQ8 variant, had been diagnosed with T1D for two years or less, and who still continued to produce some endogenous insulin. The trial was carried out at the Barbara Davis Center for Childhood Diabetes at the Univerity of Colorado School of Medicine.

    The results showed that oral methyldopa therapy given three times daily was well tolerated and didn't cause any serious adverse events. Tests indicated that the treatment specifically inhibited DQ8 antigen presentation and reduced inflammatory insulin-specific T-cell responses. Patients receiving oral methyldopa therapy three times a day exhibited good glycemic control at the end of the three-month study, and also maintained residual endogenous insulin production. “Although short-term, these results suggest methyldopa treatment may limit beta-cell destruction and preserve function…,” the authors claim.

    They acknowledge that “longer-term placebo-controlled trials are warranted to evaluate methyldopa in potentially preserving residual beta-cell function in those at-risk and with new-onset T1D.” Nevertheless, they state, “the ability to identify HLA allele-specific drugs has broad applicability to treating autoimmunity and other HLA-associated conditions.…As many autoimmune diseases are associated with specific HLA alleles and high-resolution crystal structures exist for many of these MHC class II molecules, rapid strategies to select HLA allele-specific compounds and test activities in experimental systems can occur.”

    The next stage will be a larger clinical trial during the first half of next year, sponsored by the National Institutes of Health.

    “We made this discovery using a supercomputer, on the lab bench, in mice and in humans,” Michels comments. "We can now predict with almost 100% accuracy who is likely to get T1D. The goal with this drug is to delay or prevent the onset of the disease among those at risk."

    Michels and co-author David Ostrov, Ph.D., hope that the same treatment approach could have more widespread use. "This study has significant implications for treatment of diabetes and also other autoimmune diseases," said Ostrov, associate professor at the University of Florida College of Medicine's Center for NeuroGenetics. "This study suggests that the same approach may be adapted to prevent autoimmune diseases such as rheumatoid arthritis, celiac disease, multiple sclerosis, systemic lupus erythematosus, and others."


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