Old Blood Pressure Drug: Hope for Type 1 Diabetes Prevention?

Liam Davenport

February 28, 2018

A drug widely used for over 50 years to control blood pressure may prevent type 1 diabetes and even help treat patients who have the disease by preventing the autoimmune destruction of insulin-producing pancreatic beta cells, suggest US researchers after conducting a search of pre-existing drugs.

Focusing on an immune protein linked to the development of type 1 diabetes present in up to 60% of patients, the team initially identified a candidate molecule for preventing the disease based on its three-dimensional structure and fit with the DQ8 allele.

They then trawled through more than 1500 drugs already approved by the US Food and Drug Administration (FDA) using a sophisticated program to find similar shaped drugs.

Eventually, they identified methyldopa, a well-established antihypertensive drug.

Studying the drug in 20 patients recently diagnosed with type 1 diabetes, the team found that methyldopa not only blocked the immune activity of the DQ8 allele, but also appeared to stabilize disease.

The research was published online February 13 in the Journal of Clinical Investigation.

"This is the first personalized treatment for type 1 diabetes prevention," said senior author Aaron Michels, MD, Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, in a press release by his institution.

"With this drug, we can potentially prevent up to 60% of type 1 diabetes in those at risk for the disease. This is a very significant development."

Lead author David A Ostrov, PhD, College of Medicine, University of Florida, Gainesville, noted that the techniques used in the study may also offer opportunities to identify novel treatments for other autoimmune diseases, such as rheumatoid arthritis, celiac disease, and lupus.

In the meantime, the team will build on their findings by conducting a clinical trial of methyldopa for the prevention and treatment of type 1 diabetes funded by the National Institutes of Health (NIH).

Michels told Medscape Medical News that the TN-23 study will be a multicenter, randomized, placebo-controlled crossover trial of children and adolescents at risk of type 1 diabetes who have the immune protein, and will assess the safety, efficacy, and mode of action of methyldopa in preventing antigen presentation.

Proof-of-Concept Trial

Although reduced insulin production in type 1 diabetes is widely believed to be caused by the autoimmune-mediated destruction of pancreatic beta cells, immune therapies tested so far have offered limited clinical benefits.

Research over the past decade has shown, however, that DQ8, a gene in the human leukocyte antigen (HLA) complex linked to autoreactive T-cell responses, is present in 50% to 60% of patients with type 1 diabetes and increases the risk of developing the disease by up to 11-fold.

Hypothesizing that the DQ8 allele may be a novel treatment target, researchers used its three-dimensional structure to screen a library of 139 735 small molecules for those that could bind to structural pockets in the allele and block antigen presentation.

The ability of the top 40 scoring compounds to alter insulin/DQ8-specific T-cell responses was then assessed in vitro using a T-cell bioassay and revealed that one compound, tetraazatricyclododecane (TATD), interacted directly with the peptide/DQ8 complex without causing cell cytotoxicity.

Subsequent administration of TATD to nonobese diabetic mice was found to block major histocompatibility complex (MHC) class II antigen presentation.

Moreover, the compound prevented or delayed diabetes onset, blocked T-/B-cell interactions, reduced tissue-specific destruction, and maintained glucose tolerance in mice with the disease.

To see if an existing drug could have the same effects, the team then screened 1207 small molecule drugs already approved by the FDA to identify those that could potentially occupy the same binding pocket as TATD on the DQ8 allele.

Ten of 39 top-scoring drugs showed promise, of which one, methyldopa, inhibited T-cell responsiveness in vitro. Moreover, the drug blocked antigen presentation by DQ8 in a dose-dependent manner and prevented other peptides binding to the allele without causing cell cytotoxicity.

Having also shown that methyldopa prevented DQ8 antigen presentation in nonobese diabetic mice, the team conducted a single-arm, open-label phase 1b dose-escalation study in 20 patients with type 1 diabetes of less than 2 years' duration who still produced endogenous insulin and were positive for DQ8.

To prevent hypotension, the patients were given three oral doses of methyldopa over 6 weeks, which was well-tolerated with no serious adverse events.

Low, moderate, and high doses of methyldopa resulted in a significant 40% reduction in DQ8 antigen presentation by peripheral blood mononuclear cells vs baseline levels, and 17 patients responded.

Furthermore, methyldopa was associated with reductions in insulin-specific CD4 T-cell responses in the peripheral circulation.

Glycemic control also remained steady over 3 months, with no changes in total insulin doses, and residual endogenous insulin production remained similar to baseline. This contrasts with findings from natural history studies, which suggest that patients with type 1 diabetes experience a steady decline in insulin production after diagnosis.

Describing the study as a proof-of-concept trial, the team writes: "Although short-term, these results suggest methyldopa treatment may limit beta-cell destruction and preserve function; however, trials with a longer duration and placebo arm are needed to fully evaluate metabolic efficacy."

Although they acknowledge that there are "several concerns" about using pre-existing drugs to target MHC class II antigen presentation, researchers say that "one advantage of 'repurposing' existing drugs is that well-characterized safety profiles indicate potential complications and off-target effects."

And they note that, with more than 50 years of clinical use, methyldopa "is considered safe," even in the approximately 10% of the general European-American population carrying the DQ8 allele.

The study was supported by grants from the NIH, Juvenile Diabetes Research Foundation, Children's Diabetes Foundation, Barbara Davis Center Translational Research Unit, and Colorado Clinical and Translational Science Institute. Michels and Ostrov are inventors on a patent licensed to ImmunoMolecular Therapeutics. Michels and Gottlieb are scientific cofounders of ImmunoMolecular Therapeutics and own shares in the company. Disclosures for the other authors are listed in the article.

J Clin Invest. Published online February 13, 2018. Full text

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