title: Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1.
abstract: Adeno-associated viral (AAV) vectors (serotype 2) efficiently transduce skeletal muscle, and have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimental animals and humans. Recent reports suggest that AAV vectors based on serotypes 1, 5, and 7 transduce murine skeletal muscle much more efficiently than AAV-2, with reported increases in expression ranging from 2-fold to 1000-fold. We sought to determine whether this increased efficacy could be observed in species other than mice. In immunodeficient mice we saw 10- to 20-fold higher levels of human factor IX (hF.IX) expression at a range of doses, and in hemophilic dogs we observed approximately 50-fold higher levels of expression. The increase in transgene expression was due partly to higher gene copy number and a larger number of cells transduced at each injection site. In all immunocompetent animals injected with AAV-1, inhibitory antibodies to F.IX developed, but in immunocompetent mice treated with high doses of vector, inhibitory antibodies eventually disappeared. These studies emphasize that the increased efficacy of AAV-1 vectors carries a risk of inhibitor formation, and that further studies will be required to define doses and treatment regimens that result in tolerance rather than immunity to F.IX.
authors.affiliation: Department of Pediatrics, University of Pennsylvani Medical Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.forename: Joerg
authors.initials: J
authors.lastname: Schuettrumpf
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Nancy
authors.initials: N
authors.lastname: Robinson
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Lotfi
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Weidong
authors.initials: W
authors.lastname: Xiao
authors.forename: Linda B
authors.initials: LB
authors.lastname: Couto
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D005164:Factor IX / Q000235:genetics* / Q000276:immunology; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D002836:Hemophilia B / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D012449:Safety; D014161:Transduction, Genetic
chemical_list: D000910:Antibodies, Heterophile; D011994:Recombinant Proteins; D005164:Factor IX