RARE Daily

Scientists Find Cause, and Potential Therapeutic Strategy, for Krabbe Disease

September 17, 2019

Scientists at Washington University School of Medicine in St. Louis said they have pinpointed the precise cause and a potential therapeutic strategy for Krabbe disease, a neurodegenerative condition that usually causes death by age 3.

Patients with Krabbe disease gradually lose the protective covering that insulates axons, the wiring of the nervous system. The rare condition—affecting about 1 in 100,000 births — is typically diagnosed before age 1 and progresses rapidly.

Scientists long believed that a toxic accumulation of a compound known as psychosine might be responsible for destroying myelin, the nerve insulation. Patients with the condition are missing an important protein involved in the breaking down of psychosine, but no one had been able to find the source of psychosine in Krabbe disease.

“Krabbe disease in infancy is invariably fatal,” said senior author Mark Sands, a professor of medicine. “It’s a heartbreaking neurodegenerative disease first described more than a century ago, but we still have no effective treatments. For almost 50 years, we have assumed the psychosine hypothesis was correct — that a toxic buildup of psychosine is the cause of all the problems. But we’ve never been able to prove it.”

In an article published the September 16 edition of the Proceedings of the National Academy of Sciences, Sands and his team show that mice with genetic mutations that cause Krabbe disease and Farber disease, a lethal condition that results from the loss of a different protein, have no signs of Krabbe disease. The missing protein in Farber disease is called acid ceramidase, and when it is gone, psychosine does not build up, effectively curing Krabbe disease in mice that otherwise would have it. Without the toxic buildup of psychosine, Krabbe disease did not develop in these mice.

After identifying acid ceramidase as the trigger of the toxic buildup of psychosine, Sands and his colleagues gave mice with Krabbe disease a drug known to be an acid ceramidase inhibitor. The drug, carmofur, is a common chemotherapy used to treat cancer. It modestly extended the lives of mice with a model of Krabbe disease.

Because of Camofur’s toxicity, it would not be considered a good candidate as a treatment for Krabbe, but Sands said it does suggest a therapeutic strategy for treating the disease.

“The research demonstrates a proof-of-concept that we can inhibit acid ceramidase with a drug, and it will relieve some of the symptoms of Krabbe disease,” he said. “We will need to strike a balance, though, because inhibiting it too much will cause Farber disease.”

Photo: A cross section of a normal mouse nerve cell (left) compared with a cross section of a mouse nerve cell with Krabbe disease (right), which causes the loss of this protective layer of myelin and subsequent nerve destruction.

Author: Rare Daily Staff

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