Version 1
: Received: 5 June 2024 / Approved: 5 June 2024 / Online: 6 June 2024 (07:54:06 CEST)
How to cite:
Mishra, K.; Sweetat, S.; Baraghithy, S.; Sprecher, U.; Marisat, M.; Bastu, S.; Glickstein, H.; Tam, J.; Rosenmann, H.; Weil, M.; Malfatti, E.; Kakhlon, O. The Autophagic Activator GHF-201 can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis. Preprints2024, 2024060334. https://doi.org/10.20944/preprints202406.0334.v1
Mishra, K.; Sweetat, S.; Baraghithy, S.; Sprecher, U.; Marisat, M.; Bastu, S.; Glickstein, H.; Tam, J.; Rosenmann, H.; Weil, M.; Malfatti, E.; Kakhlon, O. The Autophagic Activator GHF-201 can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis. Preprints 2024, 2024060334. https://doi.org/10.20944/preprints202406.0334.v1
Mishra, K.; Sweetat, S.; Baraghithy, S.; Sprecher, U.; Marisat, M.; Bastu, S.; Glickstein, H.; Tam, J.; Rosenmann, H.; Weil, M.; Malfatti, E.; Kakhlon, O. The Autophagic Activator GHF-201 can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis. Preprints2024, 2024060334. https://doi.org/10.20944/preprints202406.0334.v1
APA Style
Mishra, K., Sweetat, S., Baraghithy, S., Sprecher, U., Marisat, M., Bastu, S., Glickstein, H., Tam, J., Rosenmann, H., Weil, M., Malfatti, E., & Kakhlon, O. (2024). The Autophagic Activator GHF-201 can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis. Preprints. https://doi.org/10.20944/preprints202406.0334.v1
Chicago/Turabian Style
Mishra, K., Edoardo Malfatti and Or Kakhlon. 2024 "The Autophagic Activator GHF-201 can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis" Preprints. https://doi.org/10.20944/preprints202406.0334.v1
Abstract
Glycogen storage disease type III (GSDIII) is a hereditary glycogenosis caused by deficiency of the glycogen debranching enzyme (GDE), an enzyme, encoded by Agl, enabling glycogen degradation by catalyzing alpha-1,4-oligosaccharide side chain transfer and alpha-1,6-glucose cleavage. GDE deficiency causes accumulation of phosphorylase-limited dextrin, leading to liver disorder followed by fatal myopathy. We tested here the capacity of the new autophagosomal activator GHF-201 to alleviate disease burden by clearing pathogenic glycogen surcharge in the GSDIII mouse model Agl-/-. We used open field, grip strength and rotarod tests for evaluating GHF-201’s effects on locomotion, biochemistry panel to quantify hematological biomarkers, indirect calorimetry to quantify in vivo metabolism, transmission electron microscopy to quantify glycogen in muscle, and fibroblast image analysis to determine cellular features affected by GHF-201. GHF-201 was able to improve all locomotion parameters and partially reversed hypoglycemia, hyperlipidemia and liver and muscle malfunction in Agl-/- mice. Treated mice burnt carbohydrates more efficiently and showed significant improvement of aberrant ultrastructural muscle features. In GSDIII patient fibroblasts, GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling. In conclusion, GHF-201 is a viable candidate for treating GSDIII as it recovered a wide range of its pathologies in vivo, in vitro, and ex vivo.
Keywords
glycogen; glycogen storage disease type III; pharmacotherapy
Subject
Biology and Life Sciences, Endocrinology and Metabolism
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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