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New UW study offers strategy for treatment of fatal nervous system disorder

December 13, 2005

Working with mice, University of Wisconsin-Madison researchers have developed the basis for a therapeutic strategy that could provide hope for children afflicted with Krabbe's disease, a fatal nervous system disorder.

Writing this week (Dec. 12, 2005) in the Proceedings of the National Academy of Sciences (PNAS), a team of researchers at the UW-Madison School of Veterinary Medicine describes experiments that effectively promoted the ability of defective cells to take up and utilize an enzyme that is essential for the maintenance of a critical sheathing of nerve fibers.

The work centers on devising strategies to treat inherited diseases of the nervous system in which cells fail to maintain myelin, a protective sheathing that envelops nerve fibers and acts like the insulation on an electric wire. Myelin ensures the effective transmission of the signals routinely conducted by the nervous system. For those afflicted with Krabbe's disease, the loss of myelin results in arrested motor and mental development, seizures, paralysis and, ultimately, death.

The Wisconsin experiments, led by Ian Duncan, a UW-Madison professor of medical sciences who is an expert on diseases of myelin, explored how cells obtained from a mouse model of Krabbe's disease could be reinvigorated by replacing a missing enzyme, and thus allow the healthy maintenance of myelin.

In the case of Krabbe's disease, myelination begins normally in early development. But the absence in myelin-forming cells of a key enzyme known as galactocerebrosidase leads to the death of the cells and, subsequently, the loss of myelin. "Our hypothesis was that if you provided the (flawed) myelinating cells with the enzyme, the cells would maintain the myelin as healthy cells would," says Duncan, the senior author of the PNAS paper who planned and conducted the experiments with lead author Yoichi Kondo, a postdoctoral fellow working in Duncan's lab.

Simply supplying the enzyme directly to the brain and spinal cord is complicated by a natural barrier - the blood-brain barrier - that makes the delivery of agents like the enzyme to the brain difficult.

"To eliminate the barrier, we changed the paradigm by transplanting enzyme-deficient cells into the brain and spinal cord of another type of mouse which can provide the enzyme," explains Duncan.

The Wisconsin group isolated progenitor cells from the mouse model of Krabbe's disease. Transplanting the cells to the brain and spinal cord of another type of mouse that lacks any myelin, the group observed that the implanted cells took up the enzyme from the host cells and sparked widespread and persistent myelination of the brain and spinal cord.

"The donor cells are stable and survive and, biochemically, enzyme levels in the graft were restored to normal," says Kondo.

Enzyme replacement therapy, Duncan notes, is not a new idea for treating such inherited demyelinating diseases. For example, work by other groups involving transplants of bone marrow and umbilical cord blood in Krabbe's patients have been attempted with some success.

But no one knew if the missing enzyme could be replaced in key cells known as oligodendrocytes, thus allowing maintenance of stable myelin throughout the nervous system.

"This experimental strategy proves that oligodendrocytes can survive and maintain myelin when transplanted into an environment where the missing enzyme is available," says Kondo.

Krabbe's disease is perhaps best known to the public through the efforts of Hall of Fame quarterback Jim Kelly, whose late son Hunter was afflicted with the disease and who established a foundation, Hunter's Hope, to promote awareness and research. The new study was funded by Hunter's Hope.

Krabbe's disease is one of a number of diseases caused by the inability to produce and maintain myelin. It afflicts about 1 in every 100,000 people and treatment options are limited at best.

The new work, the authors emphasize, provides proof of principle for a new therapeutic strategy, but any therapy developed on the group's new insights will require further study.

University of Wisconsin-Madison