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Article Dans Une Revue Gene Therapy Année : 2023

Development of a dual hybrid AAV vector for endothelial-targeted expression of von Willebrand factor

Elena Barbon
Charlotte Kawecki
  • Fonction : Auteur
Solenne Marmier
  • Fonction : Auteur
Aboud Sakkal
  • Fonction : Auteur
Fanny Collaud
  • Fonction : Auteur
Severine Charles
  • Fonction : Auteur
Giuseppe Ronzitti
Caterina Casari
Olivier Christophe
  • Fonction : Auteur
Cécile Denis
Peter J. Lenting
Federico Mingozzi

Résumé

Abstract Von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWD represents a potential target for gene therapy applications, as a single treatment could potentially result in a long-term correction of the disease. In recent years, several liver-directed gene therapy approaches have been exploited for VWD, but their efficacy was generally limited by the large size of the VWF transgene and the reduced hemostatic activity of the protein produced from hepatocytes. In this context, we aimed at developing a gene therapy strategy for gene delivery into endothelial cells, the natural site of biosynthesis of VWF. We optimized an endothelial-specific dual hybrid AAV vector, in which the large VWF cDNA was put under the control of an endothelial promoter and correctly reconstituted upon cell transduction by a combination of trans- splicing and homologous recombination mechanisms. In addition, we modified the AAV vector capsid by introducing an endothelial-targeting peptide to improve the efficiency for endothelial-directed gene transfer. This vector platform allowed the reconstitution of full-length VWF transgene both in vitro in human umbilical vein endothelial cells and in vivo in VWD mice, resulting in long-term expression of VWF.

Dates et versions

hal-04455812 , version 1 (13-02-2024)

Identifiants

Citer

Elena Barbon, Charlotte Kawecki, Solenne Marmier, Aboud Sakkal, Fanny Collaud, et al.. Development of a dual hybrid AAV vector for endothelial-targeted expression of von Willebrand factor. Gene Therapy, 2023, 30 (3-4), pp.245-254. ⟨10.1038/s41434-020-00218-6⟩. ⟨hal-04455812⟩
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