Researchers at Duke University School of Medicine are investigating a potential biomarker to better detect and monitor central nervous system (CNS) involvement in Pompe disease, a metabolic disorder that leads to muscle weakness, respiratory failure, and heart problems.
Alglucosidase alfa (Myozyme/Lumizyme), an enzyme replacement therapy developed at Duke and approved by the FDA in 2006, remains the standard of care for treatment, but it does not cross the blood-brain barrier. This leaves CNS symptoms unaddressed as patients age. Almost all patients with Pompe disease experience sensorineural hearing loss. Other symptoms include swallowing difficulties, slow or slurred speech, foot slapping gait, and, in more severe cases, seizure and encephalopathy.
In a study led by Priya Kishnani, MD, Chen Family Distinguished Professor of Pediatrics, and published in eBioMedicine, the team evaluated glial fibrillary acidic protein (GFAP), a biomarker associated with astrocyte activity in the brain.
Astrocytes are star-shaped glial cells in the CNS that help form the structure of the brain. The GFAP biomarker may be a more CNS-specific alternative to the commonly studied neurofilament light chain, which is a non-specific early-stage biomarker used in neurodegenerative diseases. “As these children and young adults age,” Kishnani said, “they are developing signs and symptoms of CNS involvement, so we need a reliable biomarker to track this.”
Kristen Hagarty-Waite, PhD, postdoctoral associate and co-author, has been focusing on the more severe end of the disease spectrum to determine what the biomarkers look like. “This gives us an idea of a clinical trial endpoint for blood brain barrier crossing treatments,” she said, “which are currently being developed, but we need to create the infrastructure to show industry how important this is.”
The team found white matter hyperintensity – bright spots that show up in an MRI that signal damage to the white matter of the brain. “We are seeing increases in white matter hyperintensity over time in some,” Hagarty-Waite said. “So figuring out how GFAP correlates and changes over time helps us build a picture of what can happen.
Findings suggest this new biomarker may more accurately reflect the degree of neurological involvement and could serve as a valuable tool for identifying children at risk for developing CNS disease. It could also be useful in tracking disease progression and response to emerging therapies.
While the study has been retrospective in nature, the data have been vital to show the importance of GFAP as a CNS marker in Pompe disease. “This is an exciting new biomarker that could give us a more complete story that will track disease progression and treatment response.” Kishnani said.