mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease

Jingsong Cao, Minjung Choi, Eleonora Guadagnin, Maud Soty, Marine Silva, Vincent Verzieux, Edward Weisser, Arianna Markel, Jenny Zhuo, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Kristine Burke, Tatiana Ketova, Cosmin Mihai, Zach Zalinger, Becca Levy, Gilles Besin, Meredith Wolfrom, Barbara Tran, Christopher Tunkey, Erik Owen, Joe Sarkis, Athanasios Dousis, Vladimir Presnyak, Christopher Pepin, Wei Zheng, Lei Ci, Marjie Hard, Edward Miracco, Lisa Rice, Vi Nguyen, Mike Zimmer, Uma Rajarajacholan, Patrick F. Finn, Gilles Mithieux, Fabienne Rajas, Paolo G. V. Martini () and Paloma H. Giangrande ()
Additional contact information
Jingsong Cao: Rare Diseases, Moderna, Inc
Minjung Choi: Rare Diseases, Moderna, Inc
Eleonora Guadagnin: Rare Diseases, Moderna, Inc
Maud Soty: INSERM UMR1213, Université Claude Bernard Lyon 1
Marine Silva: INSERM UMR1213, Université Claude Bernard Lyon 1
Vincent Verzieux: INSERM UMR1213, Université Claude Bernard Lyon 1
Edward Weisser: Rare Diseases, Moderna, Inc
Arianna Markel: Rare Diseases, Moderna, Inc
Jenny Zhuo: Rare Diseases, Moderna, Inc
Shi Liang: Rare Diseases, Moderna, Inc
Ling Yin: Rare Diseases, Moderna, Inc
Andrea Frassetto: Rare Diseases, Moderna, Inc
Anne-Renee Graham: Platform, Moderna, Inc
Kristine Burke: Platform, Moderna, Inc
Tatiana Ketova: Platform, Moderna, Inc
Cosmin Mihai: Platform, Moderna, Inc
Zach Zalinger: Platform, Moderna, Inc
Becca Levy: Platform, Moderna, Inc
Gilles Besin: Platform, Moderna, Inc
Meredith Wolfrom: Platform, Moderna, Inc
Barbara Tran: Platform, Moderna, Inc
Christopher Tunkey: Platform, Moderna, Inc
Erik Owen: Platform, Moderna, Inc
Joe Sarkis: Platform, Moderna, Inc
Athanasios Dousis: Platform, Moderna, Inc
Vladimir Presnyak: Platform, Moderna, Inc
Christopher Pepin: Platform, Moderna, Inc
Wei Zheng: Platform, Moderna, Inc
Lei Ci: Platform, Moderna, Inc
Marjie Hard: Platform, Moderna, Inc
Edward Miracco: Platform, Moderna, Inc
Lisa Rice: Rare Diseases, Moderna, Inc
Vi Nguyen: Rare Diseases, Moderna, Inc
Mike Zimmer: Rare Diseases, Moderna, Inc
Uma Rajarajacholan: Rare Diseases, Moderna, Inc
Patrick F. Finn: Rare Diseases, Moderna, Inc
Gilles Mithieux: INSERM UMR1213, Université Claude Bernard Lyon 1
Fabienne Rajas: INSERM UMR1213, Université Claude Bernard Lyon 1
Paolo G. V. Martini: Rare Diseases, Moderna, Inc
Paloma H. Giangrande: Rare Diseases, Moderna, Inc

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Glycogen 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.

Date: 2021
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DOI: 10.1038/s41467-021-23318-2

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