Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice

Cell Stem Cell. 2007 Dec 13;1(6):646-57. doi: 10.1016/j.stem.2007.09.016.

Abstract

Duchenne muscular dystrophy (DMD) is a hereditary disease caused by mutations that disrupt the dystrophin mRNA reading frame. In some cases, forced exclusion (skipping) of a single exon can restore the reading frame, giving rise to a shorter, but still functional, protein. In this study, we constructed lentiviral vectors expressing antisense oligonucleotides in order to induce an efficient exon skipping and to correct the initial frameshift caused by the DMD deletion of CD133+ stem cells. The intramuscular and intra-arterial delivery of genetically corrected CD133 expressing myogenic progenitors isolated from the blood and muscle of DMD patients results in a significant recovery of muscle morphology, function, and dystrophin expression in scid/mdx mice. These data demonstrate that autologous engrafting of blood or muscle-derived CD133+ cells, previously genetically modified to reexpress a functional dystrophin, represents a promising approach for DMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / genetics
  • Cells, Cultured
  • Dystrophin / genetics*
  • Dystrophin / metabolism
  • Exons
  • Gene Deletion*
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Glycoproteins / genetics
  • Humans
  • Lentivirus / genetics
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / therapy*
  • Muscular Dystrophy, Duchenne / genetics*
  • Peptides / genetics
  • Stem Cell Transplantation*
  • Transplantation, Heterologous

Substances

  • AC133 Antigen
  • Antigens, CD
  • Dystrophin
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse