title: Obstacles and future of gene therapy for hemophilia.
abstract: BACKGROUND
  The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response. Emerging evidence suggests that the latter is vector-dose dependent. Furthermore, the development and eradication of inhibitors remains a significant safety concern. Similarly, biological differences between Factor VIII and Factor IX (FIX) impose challenges to direct adoption of the successes for HB to hemophilia A (HA).
  
  
  METHODS
  The advantages and limitations of the current strategies addressing these obstacles for gene therapy for HB and HA are discussed, as well as vector manufacturing issues relevant to widespread adoption. Alternative strategies including bothex-vivoandin-vivolentiviral-based methods are discussed, though we focus on AAV-based approaches because of their recent clinical success and potential.
  
  
  CONCLUSIONS
  Our opinion is that these obstacles can be overcome with current approaches, and AAV-based gene therapy for HB will likely translate into future clinical care. Innovative approaches are, however, likely needed to solve the current problems obstructing HA gene therapy.
authors.affiliation: University of Pennsylvania, The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, 5056 Colket Translational Research Center, Philadelphia, PA 19104, USA ; University of Pennsylvania, Center for Cell and Molecular Therapeutics, Philadelphia, PA 19104, USA ; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.affiliation: University of Pennsylvania, The Children's Hospital of Philadelphia, 3501 Civic Center Blvd, 5056 Colket Translational Research Center, Philadelphia, PA 19104, USA.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Samelson-Jones
keywords: adeno-associated viral; gene therapy; genetic disease; hemophilia; recombinant vectors