Marrow for Krabbe's and twitcher mice?

Marrow for Krabbe's and twitcher mice?

Enzymes occur in the body in very low concentrations and therefore might seem inconsequential, but there are some severe disorders caused by errors in enzyme metabolism. Among these is Krabbe's disease, a rare hereditary condition characterized by a deficiency of galactosylceramidase. Without this enzyme, toxic fat accumulates in the nervous system and in other body tissues. As nerves deteriorate, about four months after birth in most cases, symptoms such as seizures and vision problems appear, followed by death one or two years later. Despite the dire aspects of the disease, however, scientists have two reasons to be optimistic: a good mouse model of the disease and the encouraging results from bone marrow transplant studies, including one reported last week by a group of researchers in the Netherlands, Japan and the United States.

Like a human with Krabbe's disease, the twitcher mouse lacks galactosylceramidase, has brain tissue infiltrated with the abnormal fat-containing globoid cells, and loses the myelin sheaths around nerves. The toxic fat psychosine also accumulates in the central nervous system, and physical symptoms similar to those of Krabbe's disease develop in affected mice, which die about five weeks after birth. In recent years, scientists have used the twitcher mouse to study bone marrow transplants as a way to replace enzyme-deficient cells with normal, enzyme-producing cells. Despite some good results with restoring enzyme activity in the lung and liver, researchers have remained uncertain whether the transplanted cells could cross the selective blood-brain barrier to the tissues most affected by the lack of enzyme.

Scientists from the Netherlands' University Hospital in Leiden, the University of North Carolina in Chapel Hill and Kyushu University in Fukuoka, Japan, report in the Feb. 26 SCIENCE that they have confirmed that donor cells do migrate into the brain. Results also show that marrow transplants -- performed when the mice are 9 to 12 days old -- increase enzyme levels in the central nervous system, result in much lower levels of psychosine and are followed by a disappearance of globoid cells. Myelin around nerves is at least partially restored, say the authors.

The recent results support those from earlier studies at the John F. Kennedy Institute for Handicapped Children in Baltimore, where Hugo W. Moser and his co-workers found that twitcher mice given transplants live four to five times longer than untreated mice. Moser said in an interview that his group is currently looking for nontoxic ways to disrupt the blood-brain barrier, to allow more transplanted cells into the central nervous system. Although there are prenatal tests to detect the juvenile form of Krabbe's disease (which occurs in 1 in 40,000 live births), Moser says transplants would more likely be used in the even rarer adolescent-onset form of the disease.