ArticleDisease models & mechanisms2019
Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG.
Article in Disease models & mechanisms, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).International journal of molecular sciences · 2022Pooled it
- Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.Orphanet journal of rare diseases · 2021Trial
- Human gastric multi-regional assembloids for functional parietal maturation and patient-specific modelling of antral foveolar hyperplasia.Nature biomedical engineering · 2026Article
- Proteo-Metabolomic Profiling of PMM2-CDG Reveals Dysregulation of Retinoic Acid Synthesis, Myo-Inositol, and the Hexosamine Pathway.Journal of inherited metabolic disease · 2026Article
- Stress-induced secretory pathway disruption causes atypical metalloproteinase transport in PMM2-CDG.iScience · 2026Article
- Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.Communications medicine · 2026Article
- Personalized Drug Repurposing Screen Identifies Patient-Specific Therapeutic Candidates for Mucopolysaccharidosis Type IIIB.Journal of personalized medicine · 2026Article
- Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor.JIMD reports · 2025Article
- Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria.Science signaling · 2025Article
- Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS.bioRxiv : the preprint server for biology · 2025Article
- Approaches to diagnostic screening for congenital disorders of glycosylation and its prevalence in Japan.Journal of human genetics · 2025Review
- Epalrestat Alleviates Reactive Oxygen Species and Endoplasmic Reticulum Stress by Maintaining Glycosylation in IMS32 Schwann Cells Under Exposure to Galactosemic Conditions.International journal of molecular sciences · 2025Article
- Laboratory and physiological aspects of substitute metazoan models for in vivo pharmacotoxicological analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Article
- O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder.Cell reports · 2024Article
- Mapping the diagnostic odyssey of congenital disorders of glycosylation (CDG): insights from the community.Orphanet journal of rare diseases · 2024Article
- Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1.Nature communications · 2024Article
- A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.PLoS genetics · 2024Article
- Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.Molecular genetics and metabolism · 2024Article
- Instrumented assessment of gait disturbance in PMM2-CDG adults: a feasibility analysis.Orphanet journal of rare diseases · 2024Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.
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