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Stem Cell-Mediated Transfer of a Human Artificial Chromosome Ameliorates Muscular Dystrophy


Details
Publication Date: 
17/08/2011
Authors: 
Tedesco FS, Hoshiya H, D'Antona G, Gerli MF, Messina G, Antonini S, Tonlorenzi R, Benedetti S, Berghella L, Torrente Y, Kazuki Y, Bottinelli R, Oshimura M, Cossu G.
Citation: 
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
DOI: 
10.1126/scitranslmed.3002342
Abstract
In contrast to conventional gene therapy vectors, human artificial chromosomes
      (HACs) are episomal vectors that can carry large regions of the genome containing
      regulatory elements. So far, HACs have not been used as vectors in gene therapy
      for treating genetic disorders. Here, we report the amelioration of the
      dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD) 
      using a combination of HAC-mediated gene replacement and transplantation with
      blood vessel-associated stem cells (mesoangioblasts). We first genetically
      corrected mesoangioblasts from dystrophic mdx mice with a HAC vector containing
      the entire (2.4 Mb) human dystrophin genetic locus. Genetically corrected
      mesoangioblasts engrafted robustly and gave rise to many dystrophin-positive
      muscle fibers and muscle satellite cells in dystrophic mice, leading to
      morphological and functional amelioration of the phenotype that lasted for up to 
      8 months after transplantation. Thus, HAC-mediated gene transfer shows efficacy
      in a preclinical model of DMD and offers potential for future clinical
      translation.