Evaluation of the Landscape of Pharmacodynamic Biomarkers in GM1 and GM2 Gangliosidosis.

GM1 and GM2 gangliosidosis are inherited, progressive, neurodegenerative lysosomal disorders of variable onset and disease progression. GM1 gangliosidosis is a result of biallelic pathogenic variants in the GLB1 gene, which confer absent or reduced β-galactosidase enzyme activity and lead to the accumulation of glycoconjugates such as glycosphingolipid GM1-gangliosides. GM2 is caused by biallelic pathogenic variants in one of the three genes (HEXA, HEXB, and GM2A) which confer deficiency of β-hexosaminidase or the GM2 ganglioside activator protein, responsible for the catabolism of GM2 gangliosides. In both gangliosidoses, glycosphingolipids accumulate primarily in neurons, with subsequent neuronal death, which translates to early mortality for patients. The clinical course is commonly differentiated by age of symptom onset. To date, no disease-modifying therapy has been approved globally, and treatment is typically supportive. The lack of mature biomarker development in these diseases contributes to challenges associated with quantifying treatment response. However, recent advancements in the detection of neurodegenerative biomarkers and treatment innovation have spurred interest in biomarker identification in plasma and cerebrospinal fluid in patients with GM1 and GM2 gangliosidosis as pharmacodynamic endpoints to support clinical trials and regulatory decision-making. In this review, we assess the landscape of lipid and protein biomarkers, the extent of evidence, and propose considerations for future biomarker development to measure treatment response and support drug development in GM1 and GM2 gangliosidosis.
(Published 2025. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)