Pursuing New Direction to Understand Krabbe Disease

Krabbe disease, also called globoid cell leukodystrophy, is a rare neurological disease that afflicts newborns. It is fatal.

Co-principal investigators on the grant — co-directors of the HJKRI M. Laura Feltri, MD, professor of biochemistry and neurology, and Lawrence Wrabetz, MD, professor of neurology and biochemistry  — say the new approach focuses on the peripheral nervous system as a possible “window” into the disease.

“What’s exciting about this grant is that we are leading research on Krabbe disease in a new direction,” Feltri says. “Our research will pinpoint which cells need correction, using methods such as gene therapy, in order to cure the disease.”

At present, the only treatment for children with Krabbe disease is a bone marrow transplant.

Krabbe disease is caused by a mutation in the GALC gene, which contains instructions for the synthesis of an enzyme called galactosylceramidase. This enzyme is responsible for breaking down certain fats that accumulate in cells during the production of myelin, the fatty insulator that allows nerve cells to communicate.

Without this enzyme, those fats accumulate, ultimately damaging and destroying the nervous system. The result is a severe and ultimately fatal neurological condition in which the child loses the ability to move, chew, swallow and breathe; they also experience vision loss and seizures.

Feltri explains that bone marrow transplants are thought to enable patients to take up the healthy enzyme from the donor cells, allowing for normal stability of myelin.

“Based on our preliminary data, we have evidence that this transfer of enzyme to sick cells is inefficient or does not occur at all,” she says. “Rather, the improvement in symptoms that is seen after a bone marrow transplant may result instead from an anti-inflammatory effect and not because of this transfer.”

Using a new animal model of the disease, the researchers expect to be able to determine which cells in the peripheral nervous system are involved in Krabbe disease and by which mechanism.

“We are at an important turning point in our understanding of the mechanisms that contribute to this disease,” Feltri says. “Based on the research done here at the institute, we are finding that we need to rethink some of the previously accepted premises about Krabbe disease. This grant will allow us to continue that important work in order to ultimately develop the best therapies to treat and ultimately cure it.”

“Together with progress made at other institutions around the world to determine how to deliver the missing enzyme to the appropriate cells via gene therapy, this will bring us closer to a successful treatment for Krabbe disease and similar disorders.”

Other researchers at the HJKRI have also received NIH funding for Krabbe disease studies.

Daesung Shin, PhD, research assistant professor of biochemistry received more than $800,000 to study “Selective Galactosylceramidase Ablation to Study the Pathogenesis of Krabbe Leukodystrophy,” along with a F30 fellowship grant to Nadav I. Weinstock, a student in the MD-PhD program who is involved in the research.

Thomas J. Langan, MD, associate professor of neurology, pediatrics and physiology and biophysics, has received NIH funding to study how to enhance newborn screening for Krabbe disease.

Additionally, Wrabetz has received funding from the European Leukodystrophy Association.

Rep. Brian Higgins, who announced the funding, noted that this new direction comes about as a result of the continued investment in the HJKRI. It is one of a handful of research institutes in the world with an exclusive focus on myelin and diseases of myelin, such as multiple sclerosis, demyelinating neuropathies and leukodystrophies, and how they may be treated.

Since Feltri and Wrabetz were recruited to UB in 2011 from the San Raffaele Scientific Institute in Milan, the HJKRI has received more than $16 million in research funding. It now employs more than 40 people.

The institute, part of UB’s New York State Center of Excellence in Bioinformatics and Life Sciences, was established by Buffalo Bills Hall of Fame quarterback Jim Kelly and his wife, Jill, after their infant son, Hunter, was diagnosed with Krabbe disease. He died in 2005 at the age of 8.