Muscle-directed gene therapy for hemophilia B with more efficient and less immunogenic AAV vectors

作者：Wang L; Louboutin J P; Bell P; Greig J A; Li Y; Wu D; Wilson J M^*

来源：Journal of Thrombosis and Haemostasis, 2011, 9(10): 2009-2019.

DOI：10.1111/j.1538-7836.2011.04491.x

• adeno-associated viruses
• factor IX
• gene therapy
• hemophilia B
• muscle

Background: Adeno-associated viral vector (AAV)-mediated and muscle-directed gene therapy is a safe and non-invasive approach to treatment of hemophilia B and other genetic diseases. However, low efficiency of transduction, inhibitor formation and high prevalence of pre-existing immunity to the AAV capsid in humans remain as main challenges for AAV2-based vectors using this strategy. Vectors packaged with AAV7, 8 and 9 serotypes have improved gene transfer efficiencies and may provide potential alternatives to overcome these problems. Objective: To compare the long-term expression of canine factor IX (cFIX) levels and anti-cFIX antibody responses following intramuscular injection of vectors packaged with AAV1, 2, 5, 7, 8 and 9 capsid in immunocompetent hemophilia B mice. Results: Highest expression was detected in mice injected with AAV2/8 vector (28% of normal), followed by AAV2/9 (15%) and AAV2/7 (10%). cFIX expression by AAV2/1 only ranged from 0 to 5% of normal levels. High incidences of anti-cFIX inhibitor (IgG) were detected in mice injected with AAV2 and 2/5 vectors, followed by AAV2/1. None of the mice treated with AAV2/7, 2/8 and 2/9 developed inhibitors or capsid T cells. Conclusions: AAV7, 8 and 9 are more efficient and safer vectors for muscle-directed gene therapy with high levels of transgene expression and absence of inhibitor formation. The absence of antibody response to transgene by AAV7, 8 and 9 is independent of vector dose but may be due to the fact that these three serotypes are associated with high level distribution to, and transduction of, hepatocytes following i.m. injection.

• 出版日期2011-10