In vivo gene transfer strategies to achieve partial correction of von Willebrand disease. Academic Article uri icon

Overview

MeSH

  • Animals
  • Dependovirus
  • Genetic Vectors
  • Immunohistochemistry
  • Liver
  • Mice
  • Mice, Knockout

MeSH Major

  • Genetic Therapy
  • von Willebrand Diseases

abstract

  • von Willebrand disease (VWD), the most common hereditary coagulation disorder, results from mutations in the 52-exon gene for von Willebrand factor (VWF), which encodes an 8.4-kB cDNA. Studies with VWF cDNA plasmids have demonstrated that in vivo gene transfer to the liver will correct the coagulation dysfunction in VWF(-/-) mice, but the correction is transient. To develop gene therapy for VWF that would mediate long-term expression of the VWF cDNA in liver, we first evaluated segmental pre-mRNA trans-splicing (SPTS) with two adeno-associated virus (AAV) serotype 8 vectors, each delivering one-half of the VWF cDNA. However, although the two vectors functioned well to generate VWF multimers after infection of cells in vitro, the efficiency of SPTS was insufficient to correct the VWF(-/-) mouse in vivo. As an alternative, we assessed the ability of a lentiviral vector to transfer the intact murine VWF cDNA in vivo directly to the neonatal liver of VWF(-/-) mice, using generation of VWF multimers, bleeding time, and bleeding volume as efficacy parameters. The VWF lentivirus generated VWF multimers and partially or completely corrected the coagulation defect on a persistent basis in 33% of the treated VWF-deficient mice. On the basis of the concept that partial persistent correction with gene transfer could be beneficial in VWD patients, these observations suggest that lentiviral delivery of VWF cDNA should be explored as a candidate for gene therapy in patients with a severe form of VWD.

publication date

  • June 2012

has subject area

  • Animals
  • Dependovirus
  • Genetic Therapy
  • Genetic Vectors
  • Immunohistochemistry
  • Liver
  • Mice
  • Mice, Knockout
  • von Willebrand Diseases

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3392614

Digital Object Identifier (DOI)

  • 10.1089/hum.2011.238

PubMed ID

  • 22482515

Additional Document Info

start page

  • 576

end page

  • 588

volume

  • 23

number

  • 6