Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications
| Autor: | Richard Jude Samulski, Matthew L. Hirsch, Chengwen Li, M Wang, Kenton T. Woodard, A Crosby, Junjiang Sun |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
serum protein viruses Genetic enhancement Plasma protein binding Gene delivery Biology Hemophilia B Article Virus Mice 03 medical and health sciences Transduction (genetics) Capsid 0302 clinical medicine Cell Line Tumor Genetics Animals Humans Cytotoxic T cell Molecular Biology Serum Albumin albumin HEK 293 cells Gene Transfer Techniques AAV Genetic Therapy Dependovirus transduction gene therapy Virology 3. Good health Mice Inbred C57BL body regions HEK293 Cells 030104 developmental biology Cell culture 030220 oncology & carcinogenesis embryonic structures Cancer research Molecular Medicine Protein Binding |
| Zdroj: | Gene therapy |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2016.75 |
| Popis: | Recent hemophilia B clinical trials using adeno-associated virus (AAV) gene delivery have demonstrated much lower coagulation factor IX (FIX) production in patients compared with the high levels observed in animal models and AAV capsid-specific cytotoxic T lymphocyte response elicited at high doses of AAV vectors. These results emphasize the necessity to explore effective approaches for enhancement of AAV transduction. Initially, we found that incubation of all AAV vectors with human serum enhanced AAV transduction. Complementary analytical experiments demonstrated that human serum albumin (HSA) directly interacted with the AAV capsid and augmented AAV transduction. The enhanced transduction was observed with clinical grade HSA. Mechanistic studies suggest that HSA increases AAV binding to target cells, and that the interaction of HSA with AAV does not interfere with the AAV infection pathway. Importantly, HSA incubation during vector dialysis also increased transduction. Finally, HSA enhancement of AAV transduction in a model of hemophilia B displayed greater than a fivefold increase in vector-derived circulating FIX, which improved the bleeding phenotype correction. In conclusion, incubation of HSA with AAV vectors supports a universal augmentation of AAV transduction and, more importantly, this approach can be immediately transitioned to the clinic for the treatment of hemophilia and other diseases. |
| Databáze: | OpenAIRE |
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