Progress on many fronts in quest to cure type 1 diabetes

The need for innovative science to address type 1 diabetes only grows more urgent. The JDRF counts 1.6 million people living with the disease in the U.S., and that number is increasing rapidly.

 

A partnership advancing City of Hope science is bringing just that — hope — to patients, families and advocates. Recent years have brought a series of promising findings from investigators in the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, bolstered by funds from The Wanek Family Project for Type 1 Diabetes.

 

The Wanek Project began in 2017. Highlights from The Wanek Project’s short history have elucidated the nature of type 1 diabetes itself, pushed forward a new approach to curing the disease and suggested avenues for reversing serious side effects.

One early, foundational study has changed the way that medical science thinks about type 1 diabetes.

 

In the disease, the immune system attacks beta cells — the cells of the pancreas that produce insulin, the hormone needed to process sugar. Thus, type 1 diabetes has traditionally been considered a defect of the body’s immune defenses — classified as an autoimmune disease.

 

However, 2017 research flipped that concept on its head. City of Hope researchers identified a defect in the beta cells themselves, rather than the immune system, that triggers the immune onslaught of type 1 diabetes. In other words, when the insulin-producing beta cells fail to function properly, the immune system attacks and kills them. Another key discovery was that 50-60% of type 1 diabetes patients still have beta cells — they just don’t work sufficiently. These new insights set the table for innovations in treatment currently under development at the DMRI, focused on repairing and protecting the beta cells.

Zeroing in on the biochemical pathways involved in type 1 diabetes, Debbie Thurmond, Ph.D., arrived at a 2018 breakthrough that could be relevant to both treating and preventing the disease.

 

City of Hope’s Ruth B. & Robert K. Lanman Chair in Gene Regulation & Drug Discovery Research and the recently appointed director of the Diabetes & Metabolism Research Institute, Thurmond investigated a protein called STX4. It is normally found in the body but depletes with certain changes to the immune system. In lab studies, the investigators found that STX4 prevented beta cells from failing in the face of excessive inflammation.

 

Thurmond, also professor and founding chair in the Department of Molecular & Cellular Endocrinology, is currently working with Roep and others to translate this discovery into a gene therapy for type 1 diabetes.

Early 2020 marked a milestone for science funded by The Wanek Project. Results had come in from a first-in-humans clinical trial testing a “reverse vaccine” for type 1 diabetes. The research showed the treatment to be safe and even indicated possible benefit as a therapy.

 

The “reverse” in reverse vaccine refers to how it mutes specific immune responses rather than exciting them. This derives from a unique strategy central to efforts in the Diabetes & Metabolism Research Institute. A common way of approaching the disease is to suppress the immune system’s activity against beta cells. City of Hope researchers are pioneering another way: they instead want to retrain the body’s defenses to see beta cells as harmless, rather than suppress it, to preserve our immunity against cancer and infection.

 

Work continues apace on this effort to modify patients’ immune cells so that they tolerate insulin-producing cells, with a second clinical trial recruiting patients starting last month.

Type 1 diabetes itself doesn’t kill. Rather, it’s the disease’s side effects that threaten life and quality of life. City of Hope’s Rama Natarajan, Ph.D., the National Business Products Industry Professor in Diabetes Research, has long been interested in understanding — and undoing — these complications.

 

A 2020 study broke new ground in her investigations into metabolic memory. In this phenomenon, the body “remembers” diabetes, causing the disease’s mechanisms to continue even when blood sugar levels are kept within a healthy range.

 

Using a large clinical dataset, Natarajan, who is also professor and chair of the Department of Diabetes Complications & Metabolism, established that the process underlying metabolic memory is epigenetic — that is, pertaining to changes to the genetic code that happen during one’s lifetime. This new knowledge will inform her efforts to develop agents that can be used to prevent or reverse complications of type 1 diabetes.

Ultimately, the quest to cure type 1 diabetes might be better characterized as a quest for cures, plural.

Research by City of Hope scientists published earlier this year underlined that idea. They profiled the immune responses of children with type 1 diabetes, finding three distinct subcategories that may require distinct therapies.

 

This discovery is entirely in keeping with the direction of modern medicine. More and more, doctors are using research results as a guide to customize treatment to the specific signatures of each individual patient’s case.

City of Hope is already leading the way in applying personalized medicine to cancer. This recent breakthrough  places City of Hope at the forefront of personalized medicine for type 1 diabetes as well.