title: Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice.
abstract: BACKGROUND
  Adenoviral-based methods of gene therapy have been ineffective at providing sustained factor (F)VIII expression in outbred populations of large animal hemophilic models primarily due to the immunogenicity of these vectors. Improvements have been made in vector design leading to the development of the helper-dependent adenoviral (HD) system. Unfortunately, it remains unclear whether these modifications are sufficient to circumvent the induction of inhibitor formation associated with adenoviral gene transfer.
  
  
  OBJECTIVE
  To develop an HD vector capable of mediating sustained FVIII expression and to determine the variables that influence inhibitor development.
  
  
  METHODS
  HD vectors were constructed encoding the canine FVIII B-domain deleted transgene under the control of either the cytomegalovirus (CMV) promoter or a tissue-restricted hybrid element consisting of five HNF-1 binding sites, located upstream of the human FVIII proximal promoter. Inbred and outbred populations of hemophilic mice were treated, and monitored for vector-induced toxicity, therapeutic efficacy, and inhibitor formation.
  
  
  RESULTS
  When HD vectors utilizing the CMV promoter were administered, all hemophilic mice developed high levels of FVIII inhibitors. In contrast, vectors under the control of the HNF/FVIII element were capable of achieving sustained elevations of FVIII for over 6 months. Strain-specific differences were also observed, with outbred animals showing a greater propensity towards inhibitor development in response to treatment.
  
  
  CONCLUSIONS
  HD vectors can be used to provide long-term FVIII expression in hemophilic animals, but treatment outcome and the induction of inhibitors is dependent on a number of variables including the transgene promoter, the vector dose, and the genetic background of the host.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: B D
authors.initials: BD
authors.lastname: Brown
authors.forename: C X
authors.initials: CX
authors.lastname: Shi
authors.forename: F E M
authors.initials: FE
authors.lastname: Rawle
authors.forename: S
authors.initials: S
authors.lastname: Tinlin
authors.forename: A
authors.initials: A
authors.lastname: McKinven
authors.forename: C
authors.initials: C
authors.lastname: Hough
authors.forename: F L
authors.initials: FL
authors.lastname: Graham
authors.forename: D
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D004274:DNA, Recombinant / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005169:Factor VIII / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D004274:DNA, Recombinant; D012333:RNA, Messenger; D005169:Factor VIII