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March 14, 2023

Prediction and Prevention: A New Paradigm in Autoimmune Disease

For more than 100 years, insulin has been the only treatment for type 1 diabetes (T1D). Insulin is a lifesaving therapy, but it has a fundamental flaw: it stops the symptoms of T1D without addressing its cause.

The FDA recently approved teplizumab, a groundbreaking therapy that signals a paradigm shift in treating not only T1D but all autoimmune diseases. Teplizumab targets T1D’s root cause and can actually delay onset for up to two years — marking major progress in BRI’s push to predict, prevent, reverse and cure autoimmune diseases. “This is a landmark event for those with or at risk for T1D. It also shows, for the first time in any autoimmune disease, that it is feasible to treat a disease early, before it starts,” says Carla Greenbaum, MD, director of BRI’s Center for Interventional Immunology.

This shift toward prevention is the result of decades of critical research by many scientists around the world, including right here at BRI. TrialNet, a global research consortium dedicated to preventing T1D and stopping its progression, ran the pivotal clinical trial that led the FDA to approve teplizumab. Dr. Greenbaum was TrialNet’s chair during the prevention trial in which BRI’s clinical research team administered teplizumab and cared for research participants across a 5-state region.

Like all medical breakthroughs, teplizumab builds on many incremental findings. A key milestone was when BRI researchers identified changes in the immune system that happen years before T1D develops.

“Teplizumab is the first therapy to try to stop the changes that lead to T1D. While it doesn’t stop T1D altogether, the delay in onset is still meaningful,” Dr. Greenbaum says. “It gives people two more years without a disease that requires around-the-clock management — and the stress, health, and financial burden that comes with it.”

It will take time for T1D screening and prevention to become common practice, but this new therapy is an important first step.

“I believe this paradigm shift will, in time, change the way physicians think about autoimmunity, aiming to prevent all immune system diseases rather than lessen the symptoms,” Dr. Greenbaum says. “More importantly, it is changing the lives of people who have these diseases or are at risk for them today.”

Advances like these motivate our team to keep pushing forward by providing real-world proof that we can achieve our mission to predict, prevent, reverse and cure immune system diseases.

“We won’t stop with one therapy that delays one disease,” Dr. Greenbaum says. “We’ll double down, working to delay T1D for longer or prevent it altogether and move toward prevention in other disease areas too. We take every advance and build on it. That’s what moves us closer to our vision of a healthy immune system for everyone.”

Our clinical research team played a key role in testing teplizumab.

Moving Toward Personalized Medicines

Teplizumab, which can delay the onset of type 1 diabetes (T1D) for a median of two years, represents a seismic shift in T1D treatment. But, like all treatments, it does not work equally well for everyone. Some people developed T1D soon after taking teplizumab while others didn’t develop the disease for three years or longer.

A recent study by BRI investigators Alice Long, PhD, and Peter Linsley, PhD, aimed to learn why. They conducted a mechanistic study, which examines exactly how and why a therapy works and looks for clues into why some people respond well and others don’t.

Looking at blood samples from people who took teplizumab, Dr. Long did a deep dive into immune cells while Dr. Linsley examined RNA. Together, they found an intriguing pattern: People who had the longest delay until onset of T1D had high numbers of exhausted T cells. Exhausted T cells are T cells that are too tired to keep attacking.

“Exhausted T cells are associated with slower disease progression in people who have T1D, but it was remarkable to see that they may also play a role in delaying the disease,” Dr. Long says. “This opens the door to more questions we hope to answer, like how these cells become exhausted and if keeping them exhausted for longer could further delay or prevent T1D.”

Every insight into how diseases start and the different ways people respond to treatments moves us closer to a world where we can offer treatments geared to an individual’s unique needs.

“The deeper we dig into immunology, the clearer it becomes that we need many autoimmune disease treatments,” Dr. Long says. “There’s no one switch that turns off disease. It may take a combination of switches, and that combination won’t be the same for everyone. Mechanistic studies like this one can help us move closer to finding those personalized therapies.”

Next Steps: Prediction and Prevention of Rheumatoid Arthritis

Teplizumab is proof that BRI’s ultimate goal is possible: We can change the course of autoimmune diseases before they start.

Our team is already working to apply what we’ve learned about delaying onset of T1D to other autoimmune diseases. We’re starting with rheumatoid arthritis (RA) because we already have some clues about how to predict it.

“Decades of research in T1D have enabled us to predict the disease with nearly 100% certainty. We’re not quite there with RA,” says Jane Buckner, MD, BRI’s president and a physician-researcher who focuses on RA. “The challenge with RA is that it can occur at any time in life and the markers of disease are not the same for everyone. This makes it difficult to know when the disease will start.”

Being able to predict if and when RA will develop is important because we know early treatment leads to a better long-term outcome for patients with RA. Further, identifying factors that initiate RA will give researchers a target to stop it. At BRI, scientists are studying the specific T cells that we believe cause RA to understand where they come from and why.

“Knowing more about when and how these cells start attacking could be crucial to more precise prediction,” Dr. Buckner says. “We’re excited to be studying these T cells in tissue from joints, which should give us great insight into exactly what they’re doing and possibly even help us identify new therapeutic targets.”

The ultimate goal? Stopping RA — and all autoimmune disease — in its tracks.

“Think about eradicating smallpox or polio. Instead of treating these diseases we have found ways to prevent them through vaccination,” Dr. Buckner says. “Prevention means no one has to suffer. Prevention is the ultimate cure.”

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