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GM1 gangliosidosis is a result of biallelic pathogenic variants in the <jats:italic>GLB1<\/jats:italic> gene, which confer absent or reduced <jats:italic>\u03b2<\/jats:italic>\u2010galactosidase enzyme activity and lead to the accumulation of glycoconjugates such as glycosphingolipid GM1\u2010gangliosides. GM2 is caused by biallelic pathogenic variants in one of the three genes (<jats:italic>HEXA<\/jats:italic>, <jats:italic>HEXB<\/jats:italic>, and <jats:italic>GM2A<\/jats:italic>) which confer deficiency of <jats:italic>\u03b2<\/jats:italic>\u2010hexosaminidase 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\u2010modifying 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\u2010making. 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.<\/jats:p>","DOI":"10.1111\/cts.70176","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:25:02Z","timestamp":1741757102000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Evaluation of the Landscape of Pharmacodynamic Biomarkers in GM1 and GM2 Gangliosidosis"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1479-605X","authenticated-orcid":false,"given":"Sydney","family":"Stern","sequence":"first","affiliation":[{"name":"Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karryn","family":"Crisamore","sequence":"additional","affiliation":[{"name":"Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo\u2010Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Pacanowski","sequence":"additional","affiliation":[{"name":"Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Schuck","sequence":"additional","affiliation":[{"name":"Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology US Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2008.04.012"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2006-0588"},{"issue":"1","key":"e_1_2_11_4_1","first-page":"663","article-title":"The GM1 and GM2 Gangliosidoses: Natural History and Progress Toward Therapy","volume":"13","author":"Regier D. 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