In vivo gene transfer strategies to achieve partial correction of von willebrand disease

Lan Wang, Jonathan B. Rosenberg, Bishnu P. De, Barbara Ferris, Rui Wang, Stefano Rivella, Stephen M. Kaminsky, Ronald Crystal

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)576-588
Number of pages13
JournalHuman Gene Therapy
Volume23
Issue number6
DOIs
Publication statusPublished - 1 Jun 2012
Externally publishedYes

Fingerprint

von Willebrand Diseases
von Willebrand Factor
Genes
Complementary DNA
Trans-Splicing
RNA Precursors
Genetic Therapy
Liver
Inherited Blood Coagulation Disorders
Type 3 Von Willebrand's Disease
Dependovirus
Lentivirus
Bleeding Time

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

In vivo gene transfer strategies to achieve partial correction of von willebrand disease. / Wang, Lan; Rosenberg, Jonathan B.; De, Bishnu P.; Ferris, Barbara; Wang, Rui; Rivella, Stefano; Kaminsky, Stephen M.; Crystal, Ronald.

In: Human Gene Therapy, Vol. 23, No. 6, 01.06.2012, p. 576-588.

Research output: Contribution to journalArticle

Wang, L, Rosenberg, JB, De, BP, Ferris, B, Wang, R, Rivella, S, Kaminsky, SM & Crystal, R 2012, 'In vivo gene transfer strategies to achieve partial correction of von willebrand disease', Human Gene Therapy, vol. 23, no. 6, pp. 576-588. https://doi.org/10.1089/hum.2011.238
Wang, Lan ; Rosenberg, Jonathan B. ; De, Bishnu P. ; Ferris, Barbara ; Wang, Rui ; Rivella, Stefano ; Kaminsky, Stephen M. ; Crystal, Ronald. / In vivo gene transfer strategies to achieve partial correction of von willebrand disease. In: Human Gene Therapy. 2012 ; Vol. 23, No. 6. pp. 576-588.
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