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

被引：40

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 50 条

[41] GLYCOGEN-STORAGE DISEASE-I AND HEPATOCELLULAR TUMORS
BIANCHI, L
EUROPEAN JOURNAL OF PEDIATRICS, 1993, 152 : S63 - S70
[42] ON DIFFERING APPEARANCE OF INTRANUCLEAR AND CYTOPLASMIC GLYCOGEN IN LIVER CELLS IN GLYCOGEN STORAGE DISEASE
SHELDON, H
KERNER, I
SILVERBERG, M
JOURNAL OF CELL BIOLOGY, 1962, 13 (03): : 468 - &
[43] Liver and liver cell transplantation for glycogen storage disease type IA
Muraca, M
Burlina, AB
ACTA GASTRO-ENTEROLOGICA BELGICA, 2005, 68 (04): : 469 - 472
[44] Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV
Yi, Haiqing
Gao, Fengqin
Austin, Stephanie
Kishnani, Priya S.
Sun, Baodong
MOLECULAR GENETICS AND METABOLISM REPORTS, 2016, 9 : 31 - 33
[45] Intranasal Iloprost Prevents Tumors in a Murine Lung Carcinogenesis Model
Tennis, Meredith A.
Smith, Alex J.
Dwyer-Nield, Lori D.
Keith, Robert L.
CANCER PREVENTION RESEARCH, 2022, 15 (01) : 11 - 16
[46] Aspirin prevents tumors in a murine model of familial adenomatous polyposis
Mahmoud, NN
Dannenberg, AJ
Mestre, J
Bilinski, RT
Churchill, MR
Martucci, C
Newmark, H
Bertagnolli, MM
SURGERY, 1998, 124 (02) : 225 - 231
[47] Correction of glycogen storage disease type 1a in a mouse model by gene therapy
Zingone, A
Hiraiwa, H
Pan, CJ
Lin, BC
Chen, HW
Ward, JM
Chou, JY
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (02) : 828 - 832
[48] DETECTION OF HETEROZYGOUS CARRIERS IN GLYCOGEN STORAGE DISEASE OF THE LIVER (VONGIERKES DISEASE)
HSIA, DYY
KOT, EG
NATURE, 1959, 183 (4671) : 1331 - 1332
[49] HIGHLY EFFICACIOUS GENE THERAPY IN THE CANINE MODEL FOR GLYCOGEN STORAGE DISEASE TYPE IA
Luo, Xiaoyan
Demaster, Amanda
Crane, Bayley
Pinto, C. R.
Brown, T. T.
Kozink, D. M.
Bird, A.
Kishnani, P. S.
Koeberl, D. D.
MOLECULAR GENETICS AND METABOLISM, 2010, 99 (03) : 221 - 222
[50] Knockout mouse model of glycogen storage disease type II: enzyme therapy at the test
Bijvoet, AGA
Van de Kamp, EHM
Kroos, MA
Van Hirtum, JP
Schoneveld, JLM
Ding, JH
Yang, BZ
Visser, P
Verbeet, MP
Oostra, BA
Reuser, AJJ
Van der Ploeg, AT
EUROPEAN JOURNAL OF HUMAN GENETICS, 1998, 6 : 43 - 43

← 1 2 3 4 5 →