RARE Daily

Yale Researchers Discover Potential Treatment for Rare Degenerative Disease

July 17, 2020

Rare Daily Staff

Researchers at Yale University have uncovered a mechanism driving the rare and progressive degenerative disease Wolfram Syndrome and also a potential treatment.

Their findings appear in the July 6 edition of Proceedings of the National Academy of Sciences. 

Wolfram Syndrome is characterized by the onset of diabetes in childhood, and, in teen years, psychiatric symptoms, loss of vision, deafness, and incontinence. It affects about one in 500,000 people worldwide. Most patients die in their 30s, and there are no treatments.

The new study confirmed that calcium inside the body’s cells play a key role, and proposed a potential treatment involving two existing drugs.

While most of the body’s calcium can be found in the bones and teeth, one percent is found in solution inside cells and bodily fluids and supports a variety of critical biological functions such as muscle contraction, nerve function, and insulin secretion. It is this latter form of calcium that her lab scrutinized in relation to Wolfram Syndrome.

“Calcium is a signaling molecule,” said Barbara Ehrlich, professor of pharmacology at Yale and head of the research team. “It will signal, for instance, when insulin should be secreted.”

Calcium-binding proteins, including neuronal calcium sensor-1 (NCS-1), a protein Ehrlich’s lab has studied for the past 20 years, regulate calcium signaling. When a research group from Europe proposed that NCS-1 was involved in Wolfram syndrome pathology, Ehrlich started investigating the disease.

The researchers confirmed that when the protein Wolframin is lost in cells in the pancreas calcium signaling gets out of kilter, resulting in reduced cell viability and lower insulin secretion, which, in turn, trigger the debilitating symptoms of the disease.

The researchers tested a number of compounds for their effectiveness in restoring calcium signaling and improving cell functions, and found two drugs that worked — ibudilast and a calpain inhibitor. Ibudilast has been approved for nearly 20 years to treat asthma in South Korea and Japan, and is currently being tested in a number of clinical trials in the United States, including for possible treatment of multiple sclerosis and amyotrophic lateral sclerosis, and, in a trial underway at Yale, for COVID-19.

Ehrlich’s team will begin a mouse study within the next six months to further confirm the effectiveness of the drugs in correcting calcium signaling and preventing the progression of Wolfram Syndrome. If the results of the animal study show promise, the researchers said, they could move quickly into human trials.

Although Wolfram syndrome is a rare disease caused by genetic mutations in a single gene, it is tied to a number of other diseases that could be viable targets for this treatment, including diabetes and bipolar disorder, the researchers said.

“Some people with bipolar disorder also have mutations in Wolframin,” Ehrlich said. “This might be one of the first genetically identified mood disorders — and we will definitely be exploring this more.”

The Yale research team collaborated with Fumihiko Urano at Washington University, a leading clinical expert on Wolfram syndrome who maintains an international registry and provided the models needed for the study.

Photo: Barbara Ehrlich, professor of pharmacology at Yale

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