Article ; Online: Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.
Science translational medicine
2024 Volume 16, Issue 730, Page(s) eadf1691
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 ...
| 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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| MeSH term(s) | Mice ; Animals ; Glycogen Storage Disease Type II/drug therapy ; Glycogen Synthase/metabolism ; Glycogen Synthase/pharmacology ; Mice, Knockout ; Glycogen/metabolism ; Muscle, Skeletal/metabolism ; Enzyme Replacement Therapy/methods | |||||
| Chemical Substances | Glycogen Synthase (EC 2.4.1.11) ; Glycogen (9005-79-2) | |||||
| Language | English | |||||
| Publishing date | 2024-01-17 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 2518854-9 | |||||
| ISSN | 1946-6242 ; 1946-6234 | |||||
| ISSN (online) | 1946-6242 | |||||
| ISSN | 1946-6234 | |||||
| DOI | 10.1126/scitranslmed.adf1691 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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