In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice
Rationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained the...
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MDPI AG
2020-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/9/793 |
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| author | Marco A. Sutter Tiziana P. Cremona Izabela Nita Eleonora Cavarra Giuseppe Lungarella Eli C. Lewis Johannes C. Schittny Thomas Geiser Amiq Gazdhar |
| author_facet | Marco A. Sutter Tiziana P. Cremona Izabela Nita Eleonora Cavarra Giuseppe Lungarella Eli C. Lewis Johannes C. Schittny Thomas Geiser Amiq Gazdhar |
| author_sort | Marco A. Sutter |
| collection | DOAJ |
| description | Rationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained therapeutic levels of circulating AAT using nonviral in vivo electroporation-mediated gene transfer to the liver. Methods: In vivo intrahepatic electroporation-mediated human AAT gene transfer was performed in C57 Bl/6J mice carrying a genetic deficiency of murine AAT (pallid mice) and suffering from pulmonary emphysema. The animals were evaluated for lung function using flexiVent and detailed stereological assessments. Lung neutrophilic burden was assessed. Results: Pallid mice showed morphologically detectable pulmonary emphysema. Thirty days after in vivo electroporation-mediated gene transfer directly aimed at the liver, circulating human AAT was elevated and lung function was significantly improved compared to non-treated pallid mice. Stereological analysis revealed a reduction in pulmonary emphysema. Conclusion: Our data indicate that in vivo intrahepatic electroporation-mediated gene transfer of AAT is a safe and efficient procedure resulting in reduction of pulmonary emphysema in pallid mice. |
| first_indexed | 2024-03-10T17:00:54Z |
| format | Article |
| id | doaj.art-7e02e3d291bc4b8e8e09e6a0b265e311 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T17:00:54Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-7e02e3d291bc4b8e8e09e6a0b265e3112023-11-20T10:57:36ZengMDPI AGPharmaceutics1999-49232020-08-0112979310.3390/pharmaceutics12090793In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid MiceMarco A. Sutter0Tiziana P. Cremona1Izabela Nita2Eleonora Cavarra3Giuseppe Lungarella4Eli C. Lewis5Johannes C. Schittny6Thomas Geiser7Amiq Gazdhar8Department of Pulmonary Medicine, University Hospital Bern, 3010 Bern, SwitzerlandInstitute of Anatomy, University of Bern, 3010 Bern, SwitzerlandDepartment of Pulmonary Medicine, University Hospital Bern, 3010 Bern, SwitzerlandDepartment of Molecular and Developmental Medicine, University of Siena, 53100 Siena, ItalyDepartment of Molecular and Developmental Medicine, University of Siena, 53100 Siena, ItalyFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, IsraelInstitute of Anatomy, University of Bern, 3010 Bern, SwitzerlandDepartment of Pulmonary Medicine, University Hospital Bern, 3010 Bern, SwitzerlandDepartment of Pulmonary Medicine, University Hospital Bern, 3010 Bern, SwitzerlandRationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained therapeutic levels of circulating AAT using nonviral in vivo electroporation-mediated gene transfer to the liver. Methods: In vivo intrahepatic electroporation-mediated human AAT gene transfer was performed in C57 Bl/6J mice carrying a genetic deficiency of murine AAT (pallid mice) and suffering from pulmonary emphysema. The animals were evaluated for lung function using flexiVent and detailed stereological assessments. Lung neutrophilic burden was assessed. Results: Pallid mice showed morphologically detectable pulmonary emphysema. Thirty days after in vivo electroporation-mediated gene transfer directly aimed at the liver, circulating human AAT was elevated and lung function was significantly improved compared to non-treated pallid mice. Stereological analysis revealed a reduction in pulmonary emphysema. Conclusion: Our data indicate that in vivo intrahepatic electroporation-mediated gene transfer of AAT is a safe and efficient procedure resulting in reduction of pulmonary emphysema in pallid mice.https://www.mdpi.com/1999-4923/12/9/793alpha1 antitrypsinnonviral gene deliveryelectroporationlocalized gene deliveryemphysemaliver gene transfer |
| spellingShingle | Marco A. Sutter Tiziana P. Cremona Izabela Nita Eleonora Cavarra Giuseppe Lungarella Eli C. Lewis Johannes C. Schittny Thomas Geiser Amiq Gazdhar In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice Pharmaceutics alpha1 antitrypsin nonviral gene delivery electroporation localized gene delivery emphysema liver gene transfer |
| title | In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice |
| title_full | In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice |
| title_fullStr | In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice |
| title_full_unstemmed | In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice |
| title_short | In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice |
| title_sort | in vivo electroporation mediated intrahepatic alpha1 antitrypsin gene transfer reduces pulmonary emphysema in pallid mice |
| topic | alpha1 antitrypsin nonviral gene delivery electroporation localized gene delivery emphysema liver gene transfer |
| url | https://www.mdpi.com/1999-4923/12/9/793 |
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