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.
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 caninefactor 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 Bmice. 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: Lili Wang; Roberto Calcedo; Timothy C Nichols; Dwight A Bellinger; Aaron Dillow; Inder M Verma; James M Wilson Journal: Blood Date: 2005-01-06 Impact factor: 22.113
Authors: S Song; M Morgan; T Ellis; A Poirier; K Chesnut; J Wang; M Brantly; N Muzyczka; B J Byrne; M Atkinson; T R Flotte Journal: Proc Natl Acad Sci U S A Date: 1998-11-24 Impact factor: 11.205
Authors: R W Herzog; E Y Yang; L B Couto; J N Hagstrom; D Elwell; P A Fields; M Burton; D A Bellinger; M S Read; K M Brinkhous; G M Podsakoff; T C Nichols; G J Kurtzman; K A High Journal: Nat Med Date: 1999-01 Impact factor: 53.440
Authors: Valder R Arruda; Hansell H Stedman; Timothy C Nichols; Mark E Haskins; Matthew Nicholson; Roland W Herzog; Linda B Couto; Katherine A High Journal: Blood Date: 2004-10-12 Impact factor: 22.113
Authors: Jeffrey B Mason; Brittney L Gurda; Julie B Engiles; Kurt D Hankenson; James M Wilson; Dean W Richardson Journal: Hum Gene Ther Methods Date: 2013-06 Impact factor: 2.396
Authors: David L Mack; Karine Poulard; Melissa A Goddard; Virginie Latournerie; Jessica M Snyder; Robert W Grange; Matthew R Elverman; Jérôme Denard; Philippe Veron; Laurine Buscara; Christine Le Bec; Jean-Yves Hogrel; Annie G Brezovec; Hui Meng; Lin Yang; Fujun Liu; Michael O'Callaghan; Nikhil Gopal; Valerie E Kelly; Barbara K Smith; Jennifer L Strande; Fulvio Mavilio; Alan H Beggs; Federico Mingozzi; Michael W Lawlor; Ana Buj-Bello; Martin K Childers Journal: Mol Ther Date: 2017-02-22 Impact factor: 11.454
Authors: Lauren E Mays; Lili Wang; Jianping Lin; Peter Bell; Alison Crawford; E John Wherry; James M Wilson Journal: Mol Ther Date: 2013-06-19 Impact factor: 11.454
Authors: Jocelyn A Schroeder; Juan Chen; Yingyu Chen; Yuanhua Cai; Hongyin Yu; Jeremy G Mattson; Paul E Monahan; Qizhen Shi Journal: Blood Adv Date: 2021-03-09
Authors: Jenny A Greig; Hui Peng; Jason Ohlstein; C Angelica Medina-Jaszek; Omua Ahonkhai; Anne Mentzinger; Rebecca L Grant; Soumitra Roy; Shu-Jen Chen; Peter Bell; Anna P Tretiakova; James M Wilson Journal: PLoS One Date: 2014-11-13 Impact factor: 3.240
Authors: David H Stitelman; Tim Brazelton; Archana Bora; Jeremy Traas; Demetri Merianos; Maria Limberis; Marcus Davey; Alan W Flake Journal: Mol Ther Methods Clin Dev Date: 2014-09-10 Impact factor: 6.698