1. Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice
- Author
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Mauro Giacca, Ilaria Campagnani, Lorena Zentilin, Fabio Moda, Giorgio Giaccone, Fabrizio Tagliavini, Ileana Zucca, Michela Morbin, Chiara Vimercati, Giuseppe Legname, Margherita Ruggerone, F., Moda, C., Vimercati, I., Campagnani, M., Ruggerone, G., Giaccone, M., Morbin, L., Zentilin, Giacca, Mauro, I., Zucca, G., Legname, and F., Tagliavini
- Subjects
animal diseases ,Scrapie ,Biochemistry ,genetics, Animals, Brain ,law.invention ,immunology ,Mice ,0302 clinical medicine ,Adenoviridae ,immunology/metabolism/pathology, Genetic Vectors ,genetics/therapeutic use, HEK293 Cells, Humans, Mice, Plasmids ,genetics/therapeutic use, Prions ,immunology, Scrapie ,genetics/immunology/pathology/therapy, Single-Chain Antibodies ,genetics/immunology ,law ,genetics ,genetics/therapeutic use, Prion ,0303 health sciences ,Neurodegeneration ,Brain ,immunology/metabolism/pathology, Genetic Vector ,3. Good health ,genetics/therapeutic use ,Infectious Diseases ,genetics/therapeutic use, HEK293 Cells, Humans, Mice, Plasmid ,Recombinant DNA ,immunotherapy ,Antibody ,AAV9 ,immunology/metabolism/pathology ,Research Paper ,Plasmids ,Prions ,Genetic Vectors ,Biology ,Viral vector ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,In vivo ,medicine ,genetics/immunology/pathology/therapy ,Single-chain variable fragment ,Animals ,Humans ,030304 developmental biology ,Cell Biology ,genetics/immunology/pathology/therapy, Single-Chain Antibodie ,medicine.disease ,Virology ,In vitro ,nervous system diseases ,HEK293 Cells ,biology.protein ,030217 neurology & neurosurgery ,Single-Chain Antibodies - Abstract
Prion diseases are caused by a conformational modification of the cellular prion protein (PrP (C)) into disease-specific forms, termed PrP (Sc), that have the ability to interact with PrP (C) promoting its conversion to PrP (Sc). In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP (C) region involved in the interaction with PrP (Sc) thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP (Sc) in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding.
- Published
- 2012