IBRI Researchers Find Opportunity to Repurpose Drugs for Type 1 Diabetes

Photo courtesy of Indiana Biosciences Research Institute Diabetes Center.

More than 7% of Americans suffer from debilitating and, in some cases, life-threatening autoimmune diseases. With diagnoses on the rise, researchers continue the quest for more effective treatments and the ultimate dream – a cure. A team led by Dr. Decio Eizirik, M.D., Ph.D., Scientific Director for Indiana Biosciences Research Institute Diabetes Center, has taken a step back from the traditional immune system study approach and found potential for treatment and, theoretically, even a cure.

Eizirik met with BioSpace to share his insights on a recent collaborative study published in Science Advances this month. He believes the popular approach to autoimmune disease, studying the immune system alone, is handicapping researchers.

“We must move away from the present “immune-centric-only” view of autoimmune diseases,” Eizirik said. “Indeed, trying to understand these diseases focusing on the immune system only, and forgetting the target tissues, may be similar to attempting to fly a plane with only one wing.”

Eizirik labeled his primary focus, Type 1 diabetes, as a “disease of wrong dialogue,” where the beta cells send back signals that further stimulate the immune system. The candidate genes that increase disease risk act at a beta cell level at the target tissue – they regulate the dialogue.

For the paper, the team selected four autoimmune diseases for which they could get RNA sequencing to look at all genes the target tissue expresses. What they found was several components for the dialogue are there, and that more than 85% of the candidate genes for each disease are expressed at the target tissue level. The genes that are inhibited are mostly disease specific, but many of that genes that are in common upregulated.

What excited the team the most was that they started to find similar pathways in the diseases they looked at – type 1 diabetes, systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. This opens up the possibility for repurposing of existing, approved JAK-inhibitor drugs.

The main target of the team is TYK2, a member of the JAK family. As an intracellular enzyme, it mediates immune signaling and inflammatory signaling pathways and, in a healthy person, is an essential component of maintaining normal immune responses. TYK2 is a candidate gene for type 1 diabetes (T1D). Individuals who have a genetic disposition that causes a 50% decrease in TYK2 expression are partially protected from developing T1D.

Eizirik’s current focus then is to study the use of TYK2 inhibitor drugs in T1D, and then potentially other autoimmune diseases as well. Bristol Myers Squibb’s TYK2 inhibitor, deucravacitinib, recently announced success from a Phase III trial in patients with moderate to severe plaque psoriasis. Three JAK inhibitor drugs have already been approved by the FDA to treat rheumatoid arthritis.

Type 1 diabetes has been on the rise with a report from the CDC showing a nearly 30% increase in diagnoses in the U.S. recently. 2020 statistics show 1.4 million adults (20 years and older) and 187,000 children (under 20) are now living with T1D, a total of nearly 1.6 million Americans. The rate increasing most sharply is that of the African American and Hispanic youth populations, causing the CDC to call for “surveillance” of T1D in today’s youth populations.

This type of surveillance could be particularly helpful for where Eizirik hopes his research is going. With advanced biomarker tests that show which children have the highest potential of developing T1D in the next 5-10 years, a window is created for treatments with the potential to stop the disease from ever developing. Eizirik said his initial data suggests that treating early with a TYK2 inhibitor to protect the beta cells before they're destroyed could be effective in favoring a better outcome for these high risk individuals.

In addition to his role with Indiana Biosciences Research Institute (IBRI), Eizirik is also a professor at Universite Libre de Bruxelles, in Brussels Belgium, in the university's Center for Diabetes Research.  He spoke of his excitement over the expanding connections in the scientific community, the collaboration between researchers, the sharing of information and wealth of data access.

“This is why I felt excited to join [IBRI]. It’s something unique in the sense that it’s a translational institute. It’s not a purely academic one. This is a place where we’ve gathered people of academic background, which in my case, and people that come from industry, particularly in the area of drug development,” Eizirik said.

With the NIH requirements of depositing all raw data for any paper published, now researchers around the world have access to that data and can reanalyze and use for their own studies. The need for collaboration has been made increasingly apparent amidst a global pandemic. Biotechs and pharmaceutical companies have come together across the world to get treatments and vaccinations out to the population faster than ever before.

Eizirik hopes this global collaboration continues, leading to new therapeutics faster than ever before not just for his passion, diabetes, but all disease.

“People working in science, we couldn’t care less the color of your skin, where you come from, if you are male or female or transgender, we all really work together... This is one of the beauties of science. It’s really a transnational activity and it can only work as a transnational activity. These autoimmune diseases we’re working with affect 5% of people all across the world. We need to work together on an international basis.

“Science and viruses don’t have borders. Viruses ignore walls, so science must as well.”