Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice
Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). We show that therapeutic levels of FGF21 were achieved following subcutaneous (s.c.) administration of mRNA encoding human FGF21 proteins. The efficac...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122000865 |
| _version_ | 1828722629771526144 |
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| author | Stefano Bartesaghi Kristina Wallenius Daniel Hovdal Mathias Liljeblad Simonetta Wallin Niek Dekker Louise Barlind Nigel Davies Frank Seeliger Maria Sörhede Winzell Sima Patel Matt Theisen Luis Brito Nils Bergenhem Shalini Andersson Xiao-Rong Peng |
| author_facet | Stefano Bartesaghi Kristina Wallenius Daniel Hovdal Mathias Liljeblad Simonetta Wallin Niek Dekker Louise Barlind Nigel Davies Frank Seeliger Maria Sörhede Winzell Sima Patel Matt Theisen Luis Brito Nils Bergenhem Shalini Andersson Xiao-Rong Peng |
| author_sort | Stefano Bartesaghi |
| collection | DOAJ |
| description | Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). We show that therapeutic levels of FGF21 were achieved following subcutaneous (s.c.) administration of mRNA encoding human FGF21 proteins. The efficacy of mRNA was assessed following 2-weeks repeated s.c. dosing in diet-induced obese (DIO), mice which resulted in marked decreases in body weight, plasma insulin levels, and hepatic steatosis. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of several studies in both lean and DIO mice showed that mRNA encoding human proteins provided improved therapeutic coverage over recombinant dosed proteins in vivo. This study is the first example of s.c. mRNA therapy showing pre-clinical efficacy in a disease-relevant model, thus, showing the potential for this modality in the treatment of chronic diseases, including T2D and NASH. |
| first_indexed | 2024-04-12T11:31:16Z |
| format | Article |
| id | doaj.art-870f12a5c5cf429dbef9b12f15e31262 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-12T11:31:16Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-870f12a5c5cf429dbef9b12f15e312622022-12-22T03:35:01ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128500513Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese miceStefano Bartesaghi0Kristina Wallenius1Daniel Hovdal2Mathias Liljeblad3Simonetta Wallin4Niek Dekker5Louise Barlind6Nigel Davies7Frank Seeliger8Maria Sörhede Winzell9Sima Patel10Matt Theisen11Luis Brito12Nils Bergenhem13Shalini Andersson14Xiao-Rong Peng15Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenDiscovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenDiscovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenAdvanced Drug Delivery, Pharmaceutical Science, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenClinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, SwedenModerna, Inc., 200 Technology Square, Cambridge, MA 02139, USAModerna, Inc., 200 Technology Square, Cambridge, MA 02139, USAModerna, Inc., 200 Technology Square, Cambridge, MA 02139, USABusiness Development, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USAOligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenMetabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, Sweden; Corresponding author Xiao-Rong Peng, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-43183, Sweden.Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). We show that therapeutic levels of FGF21 were achieved following subcutaneous (s.c.) administration of mRNA encoding human FGF21 proteins. The efficacy of mRNA was assessed following 2-weeks repeated s.c. dosing in diet-induced obese (DIO), mice which resulted in marked decreases in body weight, plasma insulin levels, and hepatic steatosis. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of several studies in both lean and DIO mice showed that mRNA encoding human proteins provided improved therapeutic coverage over recombinant dosed proteins in vivo. This study is the first example of s.c. mRNA therapy showing pre-clinical efficacy in a disease-relevant model, thus, showing the potential for this modality in the treatment of chronic diseases, including T2D and NASH.http://www.sciencedirect.com/science/article/pii/S2162253122000865mRNA therapyLNPFGF21insulin resistancesteatosisDIO mice |
| spellingShingle | Stefano Bartesaghi Kristina Wallenius Daniel Hovdal Mathias Liljeblad Simonetta Wallin Niek Dekker Louise Barlind Nigel Davies Frank Seeliger Maria Sörhede Winzell Sima Patel Matt Theisen Luis Brito Nils Bergenhem Shalini Andersson Xiao-Rong Peng Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice Molecular Therapy: Nucleic Acids mRNA therapy LNP FGF21 insulin resistance steatosis DIO mice |
| title | Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice |
| title_full | Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice |
| title_fullStr | Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice |
| title_full_unstemmed | Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice |
| title_short | Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice |
| title_sort | subcutaneous delivery of fgf21 mrna therapy reverses obesity insulin resistance and hepatic steatosis in diet induced obese mice |
| topic | mRNA therapy LNP FGF21 insulin resistance steatosis DIO mice |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122000865 |
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