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

被引：41

作者：

Cao, Jingsong ^{[1
]}

Choi, Minjung ^{[1
]}

Guadagnin, Eleonora ^{[1
]}

Soty, Maud ^{[2
]}

Silva, Marine ^{[2
]}

Verzieux, Vincent ^{[2
]}

Weisser, Edward ^{[1
]}

Markel, Arianna ^{[1
]}

Zhuo, Jenny ^{[1
]}

Liang, Shi ^{[1
]}

Yin, Ling ^{[1
]}

Frassetto, Andrea ^{[1
]}

Graham, Anne-Renee ^{[3
]}

Burke, Kristine ^{[3
]}

Ketova, Tatiana ^{[3
]}

Mihai, Cosmin ^{[3
]}

Zalinger, Zach ^{[3
]}

Levy, Becca ^{[3
]}

Besin, Gilles ^{[3
]}

Wolfrom, Meredith ^{[3
]}

Tran, Barbara ^{[3
]}

Tunkey, Christopher ^{[3
]}

Owen, Erik ^{[3
]}

Sarkis, Joe ^{[3
]}

Dousis, Athanasios ^{[3
]}

Presnyak, Vladimir ^{[3
]}

Pepin, Christopher ^{[3
]}

Zheng, Wei ^{[3
]}

Ci, Lei ^{[3
]}

Hard, Marjie ^{[3
]}

Miracco, Edward ^{[3
]}

Rice, Lisa ^{[1
]}

Vi Nguyen ^{[1
]}

Zimmer, Mike ^{[1
]}

Rajarajacholan, Uma ^{[1
]}

Finn, Patrick F. ^{[1
]}

Mithieux, Gilles ^{[2
]}

Rajas, Fabienne ^{[2
]}

Martini, Paolo G., V ^{[1
]}

Giangrande, Paloma H. ^{[1
]}

机构：

[1] Moderna Inc, Rare Dis, Cambridge, MA 02139 USA

[2] Univ Claude Bernard Lyon 1, UMR1213, INSERM, Lyon, France

[3] Moderna Inc, Cambridge, MA USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

HEPATOCELLULAR ADENOMA FORMATION; GENE-THERAPY; GLUCOSE-6-PHOSPHATASE GENE; REPLACEMENT THERAPY; BLOOD-GLUCOSE; CELL THERAPY; MOUSE MODEL; 1A; IA; MUTATIONS;

D O I：

10.1038/s41467-021-23318-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-alpha). G6Pase-alpha 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((R))/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-alpha 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. Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-alpha) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-alpha delivery therapy that is efficacious and safe in a mouse model of GSD1a.

引用

页数：14

共 69 条

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