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

Jingsong Cao (1) , Minjung Choi (1) , Eleonora Guadagnin (1) , Maud Soty (2) , Marine Silva (2) , Vincent Verzieux (2) , Edward Weisser (1) , Arianna Markel (1) , Jenny Zhuo (1) , Shi Liang (1) , Ling Yin (1) , Andrea Frassetto (1) , Anne-Renee Graham (3) , Kristine Burke (3) , Tatiana Ketova (3) , Cosmin Mihai (3) , Zach Zalinger (3) , Becca Levy (3) , Gilles Besin (3) , Meredith Wolfrom (3) , Barbara Tran (3) , Christopher Tunkey (3) , Erik Owen (3) , Joe Sarkis (3) , Athanasios Dousis (3) , Vladimir Presnyak (3) , Christopher Pepin (3) , Wei Zheng (3) , Lei Ci (3) , Marjie Hard (3) , Edward Miracco (3) , Lisa Rice (1) , Vi Nguyen (1) , Mike Zimmer (1) , Uma Rajarajacholan (1) , Patrick Finn (1) , Gilles Mithieux (2) , Fabienne Rajas (2) , Paolo Martini (1) , Paloma Giangrande (1)

1 Moderna Inc - Rare Diseases [Cambridge, MA, USA]
2 NUDICE - Nutrition, diabète et cerveau
3 Moderna Inc - Platform [Cambridge, MA, USA]

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.

Domains: Neurons and Cognition [q-bio.NC]

Jingsong Cao, Minjung Choi, Eleonora Guadagnin, Maud Soty, Marine Silva, et al.. mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease. Nature Communications, 2021, 12 (1), pp.3090. ⟨10.1038/s41467-021-23318-2⟩. ⟨inserm-03257867⟩