Krabbe disease: Rosenau Family Research Foundation funds UB research focused on new therapeutic target

BUFFALO, N.Y. – A University at Buffalo researcher working on Krabbe disease (KD) has been awarded a $250,000 grant from the Rosenau Family Research Foundation to investigate how an enzyme deficiency in the brain causes this disease, which is usually fatal by age 2.

The two-year grant will fund the work of Daesung Shin, PhD, assistant professor in the Department of Biotechnical and Clinical Laboratory Sciences in the Jacobs School of Medicine and Biomedical Sciences at UB.

KD is an inherited disorder that destroys the myelin sheath, the protective coating of nerve cells in the brain and throughout the nervous system. Symptoms, including paralysis and blindness, typically develop in babies before 6 months of age, and it’s usually fatal by age 2. KD can occur in older children and adults, when the course of the disease can vary greatly.

It is known that KD is caused by a deficiency of galactosylceramidase (GALC), an enzyme that breaks down galactosylceramide, an important component of myelin, which ensures the rapid transmission of nerve impulses.

However, Shin says, there has been a lack of understanding of how the GALC deficiency leads to the symptoms of KD. He and his colleagues, working in UB’s Department of Biotechnical and Clinical Laboratory Sciences, have found that a type of overactive signaling in the brain may be responsible for causing the disease.

“We have evidence that the signaling of hyperactive nuclear factor-kappa B(NF-kB), a family of proteins that acts like a switch to control which genes are turned on for inflammation, in the Krabbe brain is contributing to the phenotype we observe,” says Shin. “This grant from the Rosenau Family Research Foundation will help us to determine if targeting the NF-kB pathway could offer a promising therapeutic avenue for Krabbe disease.”

Shin says that the objective of the research is to characterize the inflammation triggered by GALC deficiency in both oligodendrocytes — the cells that produce myelin — and the brain’s immune cells called microglia.

“This grant will allow us to investigate the mechanistic contributions of NF-kB signaling in Krabbe pathogenesis,” explains Shin. “Our findings will illuminate the causes of Krabbe disease and ultimately allow novel therapeutic strategies to be developed.”

The long-term goal is a better understanding of the cell-specific effects of GALC deficiency and other critical molecules involved in KD, which, when combined with currently available treatments such as gene therapy and cell transplantation, could lead to new therapeutic strategies.

In addition, Shin says the team will be investigating what he says is the intriguing concept of oligodendrocytes as regulators of neuroinflammation.

“This relatively recent but increasingly significant idea in the field has the potential to address critical questions on detailed mechanisms of neuroinflammatory and demyelinating diseases, such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease,” says Shin.