C-reactive protein (CRP) is essential for efficient systemic transduction of recombinant adeno-associated virus vector 1 (rAAV-1) and rAAV-6 in mice
| Autor: | Jérôme Denard, Beatrice Marolleau, Thomas Voit, Fedor Svinartchouk, Tata Nageswara Rao, Hans Joerg Fehling, Christine Jenny |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Genetic enhancement viruses Immunology Blotting Western Genetic Vectors medicine.disease_cause Real-Time Polymerase Chain Reaction Microbiology Virus law.invention 03 medical and health sciences Transduction (genetics) Mice Gene Delivery 0302 clinical medicine law Transduction Genetic Virology medicine Animals Humans Immunoprecipitation RNA Messenger Luciferases Muscle Skeletal Adeno-associated virus 030304 developmental biology Mice Knockout 0303 health sciences biology Reverse Transcriptase Polymerase Chain Reaction Dependovirus Blood proteins 3. Good health Mice Inbred C57BL C-Reactive Protein 030220 oncology & carcinogenesis Insect Science biology.protein Recombinant DNA Tissue tropism Antibody |
| Zdroj: | Journal of virology. 87(19) |
| ISSN: | 1098-5514 |
| Popis: | The clinical relevance of gene therapy using the recombinant adeno-associated virus (rAAV) vectors often requires widespread distribution of the vector, and in this case, systemic delivery is the optimal route of administration. Humoral blood factors, such as antibodies or complement, are the first barriers met by the vectors administered systemically. We have found that other blood proteins, galectin 3 binding protein (G3BP) and C-reactive protein (CRP), can interact with different AAV serotypes in a species-specific manner. While interactions of rAAV vectors with G3BP, antibodies, or complement lead to a decrease in vector efficacy, systemic transduction of the CRP-deficient mouse and its respective control clearly established that binding to mouse CRP (mCRP) boosts rAAV vector 1 (rAAV-1) and rAAV-6 transduction efficiency in skeletal muscles over 10 times. Notably, the high efficacy of rAAV-6 in CRP-deficient mice can be restored by reconstitution of the CRP-deficient mouse with mCRP. Human CRP (hCRP) does not interact with either rAAV-1 or rAAV-6, and, consequently, the high efficiency of mCRP-mediated muscle transduction by these serotypes in mice cannot be translated to humans. No interaction of mCRP or hCRP was observed with rAAV-8 and rAAV-9. We show, for the first time, that serum components can significantly enhance rAAV-mediated tissue transduction in a serotype- and species-specific manner. Bioprocessing in body fluids should be considered when transfer of a preclinical proof of concept for AAV-based gene therapy to humans is planned. |
| Databáze: | OpenAIRE |
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