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

• DOI: 10.1038/s41467-021-23318-2
• Publication Date: 2021-05-25T10:02:59Z
• Authors: 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
• Keywords: Male; Science; Article; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; RNA, Messenger; Triglycerides; Mice, Knockout; 0303 health sciences; Q; Genetic Therapy; Glycogen Storage Disease; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Treatment Outcome; Liver; Glucose-6-Phosphatase; Cytokines; Nanoparticles; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Glycogen; HeLa Cells

Abstract Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) carcinomas (HCCs). There no treatment the current standard-of-care managing (Glycosade ® /modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy gene are not ideal options due challenges in drug-delivery, efficacy, safety. To develop new capable addressing both risk, we encapsulated engineered mRNAs encoding human lipid nanoparticles. We demonstrate efficacy safety our approach preclinical murine model that phenotypically resembles condition, thus presenting potential could have significant therapeutic impact on GSD1a.