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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Published inPharmaceutics Vol. 12; no. 9; p. 793
Main Authors Sutter, Marco, Cremona, Tiziana, Nita, Izabela, Cavarra, Eleonora, Lungarella, Giuseppe, Lewis, Eli, Schittny, Johannes, Geiser, Thomas, Gazdhar, Amiq
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 21.08.2020
MDPI
Subjects
Abdomen
alpha1 antitrypsin
Automation
Compliance
Digital cameras
electroporation
emphysema
Fentanyl
Gene therapy
Liver
liver gene transfer
localized gene delivery
Mutation
nonviral gene delivery
Plasmids
United States > US
Italy
Germany
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Summary: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.
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These authors contributed equally to this work.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics12090793