ArticleScientific reports2021
Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 18 citations in OpenAlex.
- Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism.bioRxiv : the preprint server for biology · 2026Article
- Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease.Journal of inherited metabolic disease · 2026Article
- In Vitro Screening of an FDA-Approved Chemical Library for Arylsulfatase A Using Fibroblast Cells Derived From Patients With MLD.BioMed research international · 2026Article
- Molecular Dynamics Simulations of 4Computational and structural biotechnology journal · 2026Article
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- Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.Journal of neuroimmunology · 2025Review
- Phytoconstituents of Withania somnifera (L.) Dunal (Ashwagandha) unveiled potential cerebroside sulfotransferase inhibitors: insight through virtual screening, molecular dynamics, toxicity, and reverse pharmacophore analysis.Journal of biological engineering · 2024Article
- Biochemical and molecular analysis of pediatric patients with metachromatic leukodystrophy in South China: functional characterization of five novel ARSA variants.Metabolic brain disease · 2024Article
- Article
- Article
- Upregulation of non-canonical and canonical inflammasome genes associates with pathological features in Krabbe disease and related disorders.Human molecular genetics · 2023Article
- Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Globoid Cell Leukodystrophy (Krabbe Disease): An Update.ImmunoTargets and therapy · 2023Review
- Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease.PloS one · 2022Article
- Article
- Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine.Frontiers in pediatrics · 2021Article
Corrections and comments
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition.
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