mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease
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Published:2021-05-25
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Cao Jingsong, Choi Minjung, Guadagnin Eleonora, Soty Maud, Silva Marine, Verzieux Vincent, Weisser Edward, Markel AriannaORCID, Zhuo Jenny, Liang Shi, Yin Ling, Frassetto Andrea, Graham Anne-Renee, Burke Kristine, Ketova Tatiana, Mihai Cosmin, Zalinger Zach, Levy Becca, Besin Gilles, Wolfrom Meredith, Tran Barbara, Tunkey Christopher, Owen Erik, Sarkis JoeORCID, Dousis Athanasios, Presnyak Vladimir, Pepin Christopher, Zheng Wei, Ci Lei, Hard Marjie, Miracco Edward, Rice Lisa, Nguyen Vi, Zimmer Mike, Rajarajacholan Uma, Finn Patrick F., Mithieux Gilles, Rajas Fabienne, Martini Paolo G. V., Giangrande Paloma H.ORCID
Abstract
AbstractGlycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade®/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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