Scientists appear to have solved a decades-long mystery regarding the precise biochemical pathway leading to Krabbe disease, a fatal genetic disorder in children.
Studying a mouse model with the same human illness, the researchers also identified a possible therapeutic strategy.
Patients with infantile globoid cell leukodystrophy, also known as Krabbe disease, gradually lose the protective covering that insulates axons, the wiring of the nervous system. The rare condition—which affects about 1 in 100,000 births—is typically diagnosed before age 1 and progresses rapidly. The disease results in seizures, developmental regression, and death, usually around age 3.
“Krabbe disease in infancy is invariably fatal.”
Scientists have long suspected that nerve insulation is destroyed in this disorder because of a buildup of a compound called psychosine. Patients with the inherited disorder are missing an important protein involved in breaking down psychosine. But the source of psychosine in Krabbe disease has been elusive, making the problem impossible to correct.
“Krabbe disease in infancy is invariably fatal,” says Mark S. Sands, professor of medicine at Washington University in St. Louis and senior author of the paper, which appears in PNAS.
“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.”
Surprisingly, Sands and his team proved the psychosine hypothesis correct by, essentially, giving mice another lethal genetic disease.
The scientists showed that mice harboring genetic mutations resulting in 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.
“We did not expect these mice to survive through embryonic development with the genetic alterations that cause both Farber disease and Krabbe disease,” Sands says. “We felt it was likely that the combination of these genetic problems would be lethal to the mouse embryo, or at least cause some combination of the problems characteristic of both diseases.
“Not only were the mice alive, we found that they did not have Krabbe disease—despite having the causal genetics—and we tested them for it in every way imaginable. It was shocking.”
Without the toxic buildup of psychosine, Krabbe disease did not develop in these mice, proving the 50-year-old hypothesis.
After identifying acid ceramidase as the trigger of the toxic buildup of psychosine, the researchers 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. The drug modestly extended the lives of mice with a model of Krabbe disease.
“Carmofur is quite toxic by itself, so it would never be used as a treatment for this disease, but we did show a modest therapeutic benefit,” Sands says. “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. We will need to strike a balance, though, because inhibiting it too much will cause Farber disease.”
Sands says he hopes researchers specializing in drug development will begin working toward a safe and effective acid ceramidase inhibitor for the disorder.
BioMarin Pharmaceutical; the Taylor Institute; the Inaugural Midwest Athletes Against Childhood Cancer (MACC) Fund Endowed Chair; and the National Institutes of Health funded the work.
