Time Window Narrowed for Krabbe Disease Treatment

The paper was published online in Nature Communications on Oct. 23.

Daesung Shin, PhD, assistant professor of biotechnical and clinical laboratory sciences, is the lead investigator on the research. He has also conducted research at UB’s Hunter James Kelly Research Institute (HJKRI).

KD is an inherited disorder that destroys myelin, the protective coating of nerve cells in the brain and throughout the nervous system. In most cases, signs and symptoms of KD develop in babies before 6 months of age, and the disease usually results in death by age 2. When it develops in older children and adults, the course of the disease can vary greatly.

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

Although there is no cure for KD, hematopoietic stem cell therapy (HSCT) — a therapy that makes blood cells — reduces neurologic deterioration and improves developmental advances. 

These benefits are dependent on the severity of the disease at the time the stem cells are transplanted — and are only beneficial if delivered at a clinically defined pre-symptomatic time point before symptoms appear — but the treatment has been found to prolong life for these infants as long as a few years.

“Even though it is widely accepted that early treatment is essential for the most positive outcome, the precise therapeutic window for treatment and what happens during this early time have never been elucidated,” Shin says.

To address that issue, Shin’s team used mutations to create a novel mouse model of KD.

“We engineered an inducible knockout mouse for the GALC gene deletion in specific cells at specific times, which provided us with the opportunity to directly ask when and where GALC enzyme is required for brain development,” Shin says.

“We were particularly interested in the role of early developmental GALC function,” he adds. “Our study not only revealed a key developmental process that requires GALC in the perinatal period, but also demonstrated that temporal GALC expression is likely a major contributor to brainstem development.”

The researchers found that by increasing GALC levels at or before this newly defined perinatal period they could improve the effectiveness of therapeutic interventions for KD.

“For the first time, our work showed the mechanistic evidence to explain why treatment must occur so early with the defined critical postnatal period at days 4-6 in mice, and demonstrated that temporal GALC expression during this time is a major contributor to brainstem development,” Shin says. 

Augmenting GALC levels at or prior to this newly defined period would likely improve the efficacy of therapeutic interventions for KD patients.

“While the time scale between mice and humans is considerably different, the sequence of key events in brain maturation between the two is consistent,” Shin says. 

He estimates that the mouse nervous system at postnatal days 4-6 corresponds to a gestational age of 32 weeks in humans. 

“Therefore, we anticipate that if our result is correct, then in utero treatments at, or prior to, 32 weeks should have better outcomes than conventional postnatal treatment for Krabbe babies,” Shin says.

The team will further identify which cell type needs to be targeted with therapy.

“This work will directly impact the design of novel treatment options for Krabbe disease patients,” Shin says, noting that KD studies are at the basis of research on other, more common neurodegenerative diseases, such as multiple sclerosis and Parkinson’s disease. Therefore, the team’s work will have implications beyond KD.

M. Laura Feltri, MD, and Lawrence Wrabetz, MD, professors of biochemistry and neurology in the Jacobs School and co-directors of the HJKRI, are co-authors.

Other co-authors from the Jacobs School are:

• Jacob M. Favret, research technician in the Department of Biotechnical and Clinical Laboratory Sciences
• Conlan Kreher, research technician in the Department of Biochemistry
• Nadav Isaac Weinstock, MD-PhD student in the neuroscience program

Duc Nguyen, PhD, and Ernesto R. Bongarzone, PhD, of the Department of Anatomy and Cell Biology in the College of Medicine at the University of Illinois at Chicago also participated in the research.

The project was initiated with the support from the Empire State Economic Development Fund for HJKRI, and further developed and finalized by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

The mission of the HJKRI is to unlock the mysteries of myelination in the nervous system and to find therapies for diseases of myelin. The institute is named for the son of former Buffalo Bills quarterback Jim Kelly. Hunter Kelly died at age 8 in 2005 from complications of KD. At that time, he was the longest living survivor of infantile KD.