Title: New Clinical Biomarkers for GM1 Gamgliosidosis

PROJECT SUMMARY
GM1 gangliosidosis is a lysosomal storage disease in which the key hydrolase enzyme, beta-galactosidase is
missing, resulting in toxic accumulation of gangliosides and other glycan metabolites, principally in the central
nervous system. Gangliosides are glycolipids while the glycan metabolites are derived from oligosaccharides
both accumulate due to the lack of the enzyme. Identifying these diverse glycan substrates is essential for
understanding the neurodegenerative progression of the disease. Research has shown that these metabolites
accumulate in urine and cerebral spinal fluid (CSF) and in tissues in a mouse model. This was also observed in
patients so these metabolites could potentially be used as biomarkers. To facilitate use of these metabolites as
non-invasive biomarkers, levels in urine and/or CSF should correspond to the levels in tissues. Previous
enzyme replacement therapy studies showed promising results in a GM1 Gangliosidosis mouse model.
Administering beta-galactosidase enzyme directly to the brain reduced GM1 ganglioside levels in the brain and
systemically in the liver. Here, we propose using this mouse model to confirm whether the levels of the
metabolites in urine and/or CSF reflect the changes observed in tissues following therapy. With success, these
metabolites would serve as clinical biomarkers that would be valuable for monitoring therapy in clinical trials
and diagnosing newborn patients.

Grant Number: 1R43NS139721-01A1
NIH Institute/Center: NIH
Principal Investigator: Jillian Brown