Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients
GM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gen...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-03-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426922000039 |
| _version_ | 1818330514322358272 |
|---|---|
| author | Richard W.D. Welford Herve Farine Michel Steiner Marco Garzotti Kostantin Dobrenis Claudia Sievers Daniel S. Strasser Yasmina Amraoui Peter M.A. Groenen Roberto Giugliani Eugen Mengel |
| author_facet | Richard W.D. Welford Herve Farine Michel Steiner Marco Garzotti Kostantin Dobrenis Claudia Sievers Daniel S. Strasser Yasmina Amraoui Peter M.A. Groenen Roberto Giugliani Eugen Mengel |
| author_sort | Richard W.D. Welford |
| collection | DOAJ |
| description | GM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gene and substrate reduction therapies, both of which act directly on sphingolipidosis are entering clinical trials for treatment of these disorders. Simple to use biomarkers for disease monitoring are urgently required to support and expedite these clinical trials. Here, lysosphingolipid and protein biomarkers of sphingolipidosis and neuropathology respectively, were assessed in plasma samples from 33 GM2 gangliosidosis patients, 13 GM1 gangliosidosis patients, and compared to 66 controls. LysoGM2 and lysoGM1 were detectable in 31/33 GM2 gangliosidosis and 12/13 GM1 gangliosidosis patient samples respectively, but not in any controls. Levels of the axonal damage marker Neurofilament light (NF-L) were highly elevated in both GM2 and GM1 gangliosidosis patient plasma samples, with no overlap with controls. Levels of the astrocytosis biomarker Glial fibrillary acidic protein (GFAP) were also elevated in samples from both patient populations, albeit with some overlap with controls. In GM2 gangliosidosis patient plasma NF-L, Tau, GFAP and lysoGM2 were all most highly elevated in infantile onset patients, indicating a relationship to severity and phenotype. Plasma NF-L and liver lysoGM2 were also elevated in a GM2 gangliosidosis mouse model, and were lowered by treatment with a drug that slowed disease progression. These results indicate that lysosphingolipids and NF-L/GFAP have potential to monitor pharmacodynamics and pathogenic processes respectively in GM2 and GM1 gangliosidoses patients. |
| first_indexed | 2024-12-13T13:05:10Z |
| format | Article |
| id | doaj.art-2598cb3f1138405aab2f37467293894f |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-13T13:05:10Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-2598cb3f1138405aab2f37467293894f2022-12-21T23:44:51ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-03-0130100843Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patientsRichard W.D. Welford0Herve Farine1Michel Steiner2Marco Garzotti3Kostantin Dobrenis4Claudia Sievers5Daniel S. Strasser6Yasmina Amraoui7Peter M.A. Groenen8Roberto Giugliani9Eugen Mengel10Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland; Corresponding author at: Idorsia Pharmaceuticals, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandAlbert Einstein College of Medicine, Dominick P. Purpura Dept of Neuroscience, 1410 Pelham Parkway South, Rose F Kennedy Center 616, Bronx, NY 10461, USAIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandSphinCS, Clinical Science for LSD, Geheimrat-Hummel-Platz 2, 65239 Hochheim, GermanyIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, SwitzerlandDepartment of Genetics, UFRGS, Medical Genetics Service and Biodiscovery Laboratory, HCPA, Porto Alegre, BrazilSphinCS, Clinical Science for LSD, Geheimrat-Hummel-Platz 2, 65239 Hochheim, GermanyGM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gene and substrate reduction therapies, both of which act directly on sphingolipidosis are entering clinical trials for treatment of these disorders. Simple to use biomarkers for disease monitoring are urgently required to support and expedite these clinical trials. Here, lysosphingolipid and protein biomarkers of sphingolipidosis and neuropathology respectively, were assessed in plasma samples from 33 GM2 gangliosidosis patients, 13 GM1 gangliosidosis patients, and compared to 66 controls. LysoGM2 and lysoGM1 were detectable in 31/33 GM2 gangliosidosis and 12/13 GM1 gangliosidosis patient samples respectively, but not in any controls. Levels of the axonal damage marker Neurofilament light (NF-L) were highly elevated in both GM2 and GM1 gangliosidosis patient plasma samples, with no overlap with controls. Levels of the astrocytosis biomarker Glial fibrillary acidic protein (GFAP) were also elevated in samples from both patient populations, albeit with some overlap with controls. In GM2 gangliosidosis patient plasma NF-L, Tau, GFAP and lysoGM2 were all most highly elevated in infantile onset patients, indicating a relationship to severity and phenotype. Plasma NF-L and liver lysoGM2 were also elevated in a GM2 gangliosidosis mouse model, and were lowered by treatment with a drug that slowed disease progression. These results indicate that lysosphingolipids and NF-L/GFAP have potential to monitor pharmacodynamics and pathogenic processes respectively in GM2 and GM1 gangliosidoses patients.http://www.sciencedirect.com/science/article/pii/S2214426922000039GangliosidosisNeurofilamentBiomarkerLysosomeLysosphingolipid |
| spellingShingle | Richard W.D. Welford Herve Farine Michel Steiner Marco Garzotti Kostantin Dobrenis Claudia Sievers Daniel S. Strasser Yasmina Amraoui Peter M.A. Groenen Roberto Giugliani Eugen Mengel Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients Molecular Genetics and Metabolism Reports Gangliosidosis Neurofilament Biomarker Lysosome Lysosphingolipid |
| title | Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients |
| title_full | Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients |
| title_fullStr | Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients |
| title_full_unstemmed | Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients |
| title_short | Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients |
| title_sort | plasma neurofilament light glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of gm2 and gm1 gangliosidoses patients |
| topic | Gangliosidosis Neurofilament Biomarker Lysosome Lysosphingolipid |
| url | http://www.sciencedirect.com/science/article/pii/S2214426922000039 |
| work_keys_str_mv | AT richardwdwelford plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT hervefarine plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT michelsteiner plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT marcogarzotti plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT kostantindobrenis plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT claudiasievers plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT danielsstrasser plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT yasminaamraoui plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT petermagroenen plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT robertogiugliani plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients AT eugenmengel plasmaneurofilamentlightglialfibrillaryacidicproteinandlysosphingolipidbiomarkersforpharmacodynamicsanddiseasemonitoringofgm2andgm1gangliosidosespatients |