G6PC mRNA Therapy Positively Regulates Fasting Blood Glucose and Decreases Liver Abnormalities in a Mouse Model of Glycogen Storage Disease 1a
| Autor: | Kirtika H. Asrani, Cleo Isaacs, Tayeba Khan, Lucy S. Jun, Romesh R. Subramanian, Jeremiah D. Farelli, Daniel S. Roseman, Fabienne Rajas |
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| Přispěvatelé: | Discovery Research [Cambridge, MA, USA], Alexion Pharmaceuticals, Inc. [Cambridge, MA, USA], In Vivo Pharmacology [Cambridge, MA, USA], Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarkers [Cambridge, MA, USA], Di Carlo, Marie-Ange, Nutrition, diabète et cerveau (NUDICE) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Blood Glucose Male G6PC GSD1a Fasting Hypoglycemia Gene Expression Protein Engineering Glycogen storage disease type Ia chemistry.chemical_compound Mice Drug Discovery Medicine Glycogen storage disease mRNA Mice Knockout Glycogen Metabolic disorder Fasting Glycogen Storage Disease Immunohistochemistry 3. Good health Liver Glucose-6-Phosphatase Molecular Medicine Original Article [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Metabolic Networks and Pathways medicine.medical_specialty Hypoglycemia 03 medical and health sciences Internal medicine Genetics Animals [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] RNA Messenger Molecular Biology Pharmacology Messenger RNA business.industry Genetic Therapy medicine.disease Disease Models Animal 030104 developmental biology Endocrinology chemistry enzyme replacement business Biomarkers |
| Zdroj: | Molecular Therapy Molecular Therapy, Cell Press, 2018, 26 (3), pp.814-821. ⟨10.1016/j.ymthe.2018.01.006⟩ |
| ISSN: | 1525-0016 1525-0024 |
| DOI: | 10.1016/j.ymthe.2018.01.006⟩ |
| Popis: | Glycogen storage disease type Ia (GSD1a) is an inherited metabolic disorder caused by the deficiency of glucose-6-phosphatase (G6Pase). GSD1a is associated with life-threatening hypoglycemia and long-term liver and renal complications. We examined the efficacy of mRNA-encoding human G6Pase in a liver-specific G6Pase−/− mouse model (L-G6PC−/−) that exhibits the same hepatic biomarkers associated with GSD1a patients, such as fasting hypoglycemia, and elevated levels of hepatic glucose-6-phosphate (G6P), glycogen, and triglycerides. We show that a single systemic injection of wild-type or native human G6PC mRNA results in significant improvements in fasting blood glucose levels for up to 7 days post-dose. These changes were associated with significant reductions in liver mass, hepatic G6P, glycogen, and triglycerides. In addition, an engineered protein variant of human G6Pase, designed for increased duration of expression, showed superior efficacy to the wild-type sequence by maintaining improved fasting blood glucose levels and reductions in liver mass for up to 12 days post-dose. Our results demonstrate for the first time the effectiveness of mRNA therapy as a potential treatment in reversing the hepatic abnormalities associated with GSD1a. Graphical Abstract Roseman et al. demonstrate that mRNA therapy could be a potential treatment to reverse hepatic abnormalities associated with GSD1a. The authors engineered G6PC protein to increase duration of protein expression, and mRNA-encoded G6PC enabled hepatic glucose secretion and reduction of liver glycogen, G6P, triglycerides, and liver weight in a GSD1a model. |
| Databáze: | OpenAIRE |
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