FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis
Abstract Background Acute pancreatitis (AP) presents a significant clinical challenge with limited therapeutic options. The complex etiology and pathophysiology of AP emphasize the need for innovative treatments. This study explores mRNA-based therapies delivering fibroblast growth factor 21 (FGF21)...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06129-7 |
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| author | Amaya Lopez-Pascual Eva Santamaria Nuria Ardaiz Iker Uriarte Tiffany Palmer Anne-Renee Graham Celia Gomar Roberto C. Barbero M. Ujue Latasa Maria Arechederra Jesus M. Urman Carmen Berasain Antonio Fontanellas Carlos L. del Rio Maite G. Fernandez-Barrena Paolo G.V. Martini Joshua R. Schultz Pedro Berraondo Matias A. Avila |
| author_facet | Amaya Lopez-Pascual Eva Santamaria Nuria Ardaiz Iker Uriarte Tiffany Palmer Anne-Renee Graham Celia Gomar Roberto C. Barbero M. Ujue Latasa Maria Arechederra Jesus M. Urman Carmen Berasain Antonio Fontanellas Carlos L. del Rio Maite G. Fernandez-Barrena Paolo G.V. Martini Joshua R. Schultz Pedro Berraondo Matias A. Avila |
| author_sort | Amaya Lopez-Pascual |
| collection | DOAJ |
| description | Abstract Background Acute pancreatitis (AP) presents a significant clinical challenge with limited therapeutic options. The complex etiology and pathophysiology of AP emphasize the need for innovative treatments. This study explores mRNA-based therapies delivering fibroblast growth factor 21 (FGF21) and apolipoprotein A1 (APOA1), alone and in combination, for treating experimental AP. Methods Liver-targeted lipid nanoparticles (LNP)-mRNA formulations encoding FGF21, APOA1, and a chimeric APOA1-FGF21, were first tested for protein expression and bioavailability in vitro and in mice fed a high-fat diet. Efficacy studies were performed in the caerulein-induced AP (Cer-AP) model, and a new AP model combining ethanol feeding with ethanol binge plus palmitoleic acid administration, the EtOH/POA-AP model. A single dose of the APOA1, FGF21, and APOA1-FGF21 LNP-mRNAs formulations was administered in both models. Serum levels of pancreatic lipase (LIPC), amylase (AMYL), and aspartate aminotransferase (AST), along with pancreatic tissue analyses using two histopathological scores were performed to evaluate treatment effects. Results In vitro studies demonstrated the translation and secretion of APOA1, FGF21, and APOA1-FGF21 proteins encoded by the LNP-mRNAs. In vivo, LNP-mRNA administration increased serum levels of the respective proteins in metabolically impaired (i.e. high fat diet-fed) mice. In the Cer-AP model, serum markers of pancreatic injury were similarly reduced when mice were treated with APOA1, FGF21, and APOA1-FGF21 LNP-mRNA, and this effect was also observed in the histopathological analyses. The EtOH/POA-AP model was more aggressive than the Cer-AP model. FGF21 and APOA1-FGF21 LNP-mRNAs were protective according to LIPC and AMYL serum levels, while APOA1 LNP-mRNA had little effect. On the other hand, histological improvements were more evident in mice receiving APOA1 LNP-mRNA. In the EtOH/POA-AP model, FGF21 and APOA1-FGF21 LNP-mRNAs reduced serum AST levels, indicating hepatoprotective activity. Discussion This proof-of-concept study demonstrates the potential of mRNA-based therapies delivering FGF21 and APOA1 in experimental AP. While individual treatments effectively reduced pancreatic injury, the APOA1-FGF21 fusion molecule did not exhibit superior activity. Liver-targeted LNP-mRNA administration may offer a promising approach for treating AP, leveraging endogenous production pathways for therapeutic proteins. Further research is warranted to elucidate the mechanisms underlying their therapeutic efficacy and optimize treatment regimens for clinical translation. |
| format | Article |
| id | doaj-art-72245e614cc64c03bb724f50200d6902 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-72245e614cc64c03bb724f50200d69022025-02-02T12:40:28ZengBMCJournal of Translational Medicine1479-58762025-01-0123111610.1186/s12967-025-06129-7FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitisAmaya Lopez-Pascual0Eva Santamaria1Nuria Ardaiz2Iker Uriarte3Tiffany Palmer4Anne-Renee Graham5Celia Gomar6Roberto C. Barbero7M. Ujue Latasa8Maria Arechederra9Jesus M. Urman10Carmen Berasain11Antonio Fontanellas12Carlos L. del Rio13Maite G. Fernandez-Barrena14Paolo G.V. Martini15Joshua R. Schultz16Pedro Berraondo17Matias A. Avila18Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraImmunology and Immunotherapy Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraModerna IncModerna IncImmunology and Immunotherapy Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraInstituto de Investigaciones Sanitarias de Navarra IdiSNAHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraModerna IncHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraModerna IncModerna IncInstituto de Investigaciones Sanitarias de Navarra IdiSNAHepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of NavarraAbstract Background Acute pancreatitis (AP) presents a significant clinical challenge with limited therapeutic options. The complex etiology and pathophysiology of AP emphasize the need for innovative treatments. This study explores mRNA-based therapies delivering fibroblast growth factor 21 (FGF21) and apolipoprotein A1 (APOA1), alone and in combination, for treating experimental AP. Methods Liver-targeted lipid nanoparticles (LNP)-mRNA formulations encoding FGF21, APOA1, and a chimeric APOA1-FGF21, were first tested for protein expression and bioavailability in vitro and in mice fed a high-fat diet. Efficacy studies were performed in the caerulein-induced AP (Cer-AP) model, and a new AP model combining ethanol feeding with ethanol binge plus palmitoleic acid administration, the EtOH/POA-AP model. A single dose of the APOA1, FGF21, and APOA1-FGF21 LNP-mRNAs formulations was administered in both models. Serum levels of pancreatic lipase (LIPC), amylase (AMYL), and aspartate aminotransferase (AST), along with pancreatic tissue analyses using two histopathological scores were performed to evaluate treatment effects. Results In vitro studies demonstrated the translation and secretion of APOA1, FGF21, and APOA1-FGF21 proteins encoded by the LNP-mRNAs. In vivo, LNP-mRNA administration increased serum levels of the respective proteins in metabolically impaired (i.e. high fat diet-fed) mice. In the Cer-AP model, serum markers of pancreatic injury were similarly reduced when mice were treated with APOA1, FGF21, and APOA1-FGF21 LNP-mRNA, and this effect was also observed in the histopathological analyses. The EtOH/POA-AP model was more aggressive than the Cer-AP model. FGF21 and APOA1-FGF21 LNP-mRNAs were protective according to LIPC and AMYL serum levels, while APOA1 LNP-mRNA had little effect. On the other hand, histological improvements were more evident in mice receiving APOA1 LNP-mRNA. In the EtOH/POA-AP model, FGF21 and APOA1-FGF21 LNP-mRNAs reduced serum AST levels, indicating hepatoprotective activity. Discussion This proof-of-concept study demonstrates the potential of mRNA-based therapies delivering FGF21 and APOA1 in experimental AP. While individual treatments effectively reduced pancreatic injury, the APOA1-FGF21 fusion molecule did not exhibit superior activity. Liver-targeted LNP-mRNA administration may offer a promising approach for treating AP, leveraging endogenous production pathways for therapeutic proteins. Further research is warranted to elucidate the mechanisms underlying their therapeutic efficacy and optimize treatment regimens for clinical translation.https://doi.org/10.1186/s12967-025-06129-7Acute pancreatitismRNA therapyFGF21APOA1CytoprotectionPancreatic injury |
| spellingShingle | Amaya Lopez-Pascual Eva Santamaria Nuria Ardaiz Iker Uriarte Tiffany Palmer Anne-Renee Graham Celia Gomar Roberto C. Barbero M. Ujue Latasa Maria Arechederra Jesus M. Urman Carmen Berasain Antonio Fontanellas Carlos L. del Rio Maite G. Fernandez-Barrena Paolo G.V. Martini Joshua R. Schultz Pedro Berraondo Matias A. Avila FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis Journal of Translational Medicine Acute pancreatitis mRNA therapy FGF21 APOA1 Cytoprotection Pancreatic injury |
| title | FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis |
| title_full | FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis |
| title_fullStr | FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis |
| title_full_unstemmed | FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis |
| title_short | FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis |
| title_sort | fgf21 and apoa1 mrna based therapies for the treatment of experimental acute pancreatitis |
| topic | Acute pancreatitis mRNA therapy FGF21 APOA1 Cytoprotection Pancreatic injury |
| url | https://doi.org/10.1186/s12967-025-06129-7 |
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