JDRF is honored to celebrate National DNA Day, to commemorate the day in 1953 when the structure of DNA was published. We have learned a great deal about type 1 diabetes (T1D) DNA in the 65 years since that publication. We know that genes can influence someone getting T1D. And we know what genes are responsible. A major component is the group of human leukocyte antigen (HLA) genes. HLA genes account for more than half of the genetic risk of developing T1D. Other responsible genes include the genes for insulin, and CTLA-4, which has a regulatory role in the immune response. There are still other genes that play a minor part.
HLA genes have an enormously crucial role in the immune system. They encode molecules that allow the immune cells to decide if a cell is good (i.e., self cells) or bad (non-self cells, like viruses, bacteria, or tumor cells). Unfortunately, inheriting certain versions of the HLA genes increases the probability that immune cells will attack the body’s healthy cells. When this happens, an autoimmune disorder will develop. HLA genes are associated with a number of autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, celiac disease, and T1D.
For T1D, HLA variants can increase the risk or offer protection. Let’s take the HLA gene called HLA-DQ. In T1D, HLA-DQ6 is protective. But HLA-DQ8 puts one at risk. About 50 to 60 percent of people with T1D have the HLA-DQ8 variant. The dichotomy of risk between the two variants highlights the importance of the immune system within T1D development.
A Blood Pressure Drug for T1D?
It’s one thing to understand genes, but quite another to develop a treatment that will either enhance or limit the genes’ behavior, hopefully making a difference in the lives of people with T1D. That’s what JDRF researcher Aaron Michels, M.D., from the University of Colorado, is trying to do.
HLA-DQ8 is an attractive treatment target, and Dr. Michels hypothesized that blocking the HLA-DQ8 would represent a novel pathway for treating T1D. He discovered that methyldopa—a therapy that has been used for 50 years to treat high blood pressure—could have a role in impeding HLA-DQ8 and subsequent immune destruction of beta cells.
In the clinical trial, Dr. Michels recruited people who had newly onset T1D and were HLA-DQ8-positive and gave them methyldopa for six weeks. The results were exciting (although there were only 20 people to weigh in!). Methyldopa caused a reduction in immune cell responses toward insulin, suggesting that it may limit beta cell destruction and preserve function.
JDRF not only funded the clinical trial, but also funded the investigations by Dr. Michels that uncovered the role that methyldopa might have in delaying the onset of T1D.
In 2017, Dr. Michels and Peter Gottlieb, M.D., started ImmunoMolecular (IM) Therapeutics, and, in 2019, the JDRF T1D Fund—JDRF’s innovative venture philanthropy fund—made a catalytic investment in IM Therapeutics, to bring the company to clinical trials of IMT-002, which is based on methyldopa.
To read more about Dr. Michels’s research, go to the JDRF blog here.