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

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

doi:10.1038/s41467-021-23318-2

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.

Highlights

Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α)
The conversion of glucose-6phosphate (G6P) to free glucose catalyzed by G6Pase-α is a key step in releasing glucose from the liver into the bloodstream; the absence of G6Pase-α causes GSD1a patients to suffer from life-threatening hypoglycemia during fasting[7]
Given the need for chronic therapy for the treatment of this disease, we show that mRNA therapy can address both the life-threatening hypoglycemia, as well as the long-term high risk of hepatocellular adenomas (HCAs)/hepatocellular carcinoma (HCC) associated with this disease

Summary

Introduction

Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). 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. Glycogen storage disease type1a (GSD1a) (OMIM: 232200) is caused by the deficiency of the glucose-6-phosphatase-alpha (G6Pase-α, encoded by the G6PC gene), a key enzyme that catalyzes the last step in glycogenolysis and gluconeogenesis[3,4]. Long-term hepatic complications include hepatocellular adenomas (HCAs) which, are observed in

Methods

Results

Conclusion