Skip to Content
Merck
  • mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease.

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

Nature communications (2021-05-27)
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, Paloma H Giangrande
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Glycogen Assay Kit, sufficient for 100 colorimetric or fluorometric tests
Sigma-Aldrich
Glucose-6-Phosphate Assay Kit, sufficient for 100 colorimetric tests
Sigma-Aldrich
Anti-G6PC antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
ALT Activity Assay, sufficient for 100 colorimetric or fluorometric tests