These authors contributed equally to this work.
Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy
Version of Record online: 26 SEP 2006
Journal of Thrombosis and Haemostasis
Volume 5, Issue 1, pages 16–24, January 2007
How to Cite
VANDENDRIESSCHE, T., THORREZ, L., ACOSTA-SANCHEZ, A., PETRUS, I., WANG, L., MA, L., DE WAELE, L., IWASAKI, Y., GILLIJNS, V., WILSON, J. M., COLLEN, D. and CHUAH, M. K. L. (2007), Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy. Journal of Thrombosis and Haemostasis, 5: 16–24. doi: 10.1111/j.1538-7836.2006.02220.x
- Issue online: 26 SEP 2006
- Version of Record online: 26 SEP 2006
- Received 17 May 2006, accepted 11 September 2006
- cardiovascular disease;
- factor IX;
- gene therapy;
Summary. Background: Adeno-associated viral (AAV) and lentiviral vectors are promising vectors for gene therapy for hemophilia because they are devoid of viral genes and have the potential for long-term gene expression. Objectives: To compare the performance of different AAV serotypes (AAV8 and AAV9) vs. lentiviral vectors expressing factor (F) IX. Methods and results: AAV-based and lentiviral vectors were generated that express FIX from the same hepatocyte-specific expression cassette. AAV9 transduced the liver as efficiently as AAV8 and resulted in supra-physiological FIX levels (3000–6000% of normal) stably correcting the bleeding diathesis. Surprisingly, AAV9 resulted in unprecedented and widespread cardiac gene transfer, which was more efficient than with AAV8. AAV8 and AAV9 were not associated with any proinflammatory cytokine induction, in accordance with their minimal interactions with innate immune effectors. In contrast, lentiviral transduction resulted in modest and stable FIX levels near the therapeutic threshold (1%) and triggered a rapid self-limiting proinflammatory response (interleukin-6), which probably reflected their ability to efficiently interact with the innate immune system. Conclusions: AAV8 and 9 result in significantly higher FIX expression levels and have a reduced proinflammatory risk in comparison with lentiviral vectors. The unexpected cardiotropic properties of AAV9 have implications for gene therapy for heart disease.