ArticleScience translational medicine2024
Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.
Article in Science translational medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Glycogen and Glycosylation: Friends or Foes?Biomolecules · 2026Review
- TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.Journal of translational medicine · 2026Article
- Distinct damage levels and transcriptional responses of lung in Hezuo pigs and Bama pigs during cold exposure.Animal bioscience · 2026Article
- A comprehensive discovery platform for ELOVL1 small-molecule inhibitors targeting very long-chain fatty acid synthesis in adrenoleukodystrophy.The Journal of biological chemistry · 2026Article
- Enriched Environment Suppresses Neuronal Ferroptosis Through SIRT1/AKT/GSK3β-Dependent Glycogen Metabolic Reprogramming After Cerebral Ischemia-Reperfusion.Antioxidants (Basel, Switzerland) · 2026Article
- Pompe Disease: Pathogenesis, Molecular Mechanisms, Neurological Aspects, Diagnostics and Modern Therapeutic Approaches.International journal of molecular sciences · 2026Review
- Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid.Cellular & molecular biology letters · 2026Article
- Glycogen synthase 1 promotes breast cancer progression by promoting IκBα ubiquitination and degradation independent of its canonical enzyme function.Cell communication and signaling : CCS · 2026Article
- Cardiovascular involvement in glycogen storage diseases.Nature reviews. Cardiology · 2026Review
- Management of life-threatening anaphylaxis to enzyme replacement therapy in an infant with Pompe disease: a case report and literature review.Frontiers in allergy · 2026Article
- Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy.iScience · 2025Article
- Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.bioRxiv : the preprint server for biology · 2025Article
- AI-driven framework to map the brain metabolome in three dimensions.Nature metabolism · 2025Article
- Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.Clinical and translational medicine · 2025Article
- A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Review
- Expanding therapeutic options for Pompe disease: a new small molecule inhibitor of glycogen synthase 1 (GYS1) shows preclinical promise in Pompe disease.Annals of translational medicine · 2024Article
- The European reference network for metabolic diseases (MetabERN) clinical pathway recommendations for Pompe disease (acid maltase deficiency, glycogen storage disease type II).Orphanet journal of rare diseases · 2024Review
- Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy.Molecular diagnosis & therapy · 2024Review
- Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease.American journal of physiology. Endocrinology and metabolism · 2024Article
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44 authors at 4 institutions in 1 country.
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Abstract
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.