title: Muscle-directed gene therapy for hemophilia B with more efficient and less immunogenic AAV vectors.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: L
authors: L
authors: Wang
authors: J-P
authors: JP
authors: Louboutin
authors: P
authors: P
authors: Bell
authors: J A
authors: JA
authors: Greig
authors: Y
authors: Y
authors: Li
authors: D
authors: D
authors: Wu
authors: J M
authors: JM
authors: Wilson
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000378:metabolism*