An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells

Antonio Filareto, Sarah Parker, Radbod Darabi, Luciene Borges, Michelina Iacovino, Tory Schaaf, Timothy Mayerhofer, Jeffrey S. Chamberlain, James M. Ervasti, R. Scott McIvor, Michael Kyba and Rita C. R. Perlingeiro ()
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Antonio Filareto: Lillehei Heart Institute, University of Minnesota
Sarah Parker: Lillehei Heart Institute, University of Minnesota
Radbod Darabi: Lillehei Heart Institute, University of Minnesota
Luciene Borges: Lillehei Heart Institute, University of Minnesota
Michelina Iacovino: Lillehei Heart Institute, University of Minnesota
Tory Schaaf: Lillehei Heart Institute, University of Minnesota
Timothy Mayerhofer: Lillehei Heart Institute, University of Minnesota
Jeffrey S. Chamberlain: University of Washington School of Medicine, K243b HSB, Box 357720, 1959 N.E. Pacific Street, Seattle, Washington 98195-7720, USA
James M. Ervasti: Molecular Biology and Biophysics, University of Minnesota
R. Scott McIvor: Cell Biology and Development, University of Minnesota
Michael Kyba: Lillehei Heart Institute, University of Minnesota
Rita C. R. Perlingeiro: Lillehei Heart Institute, University of Minnesota

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin–glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiate these cells into skeletal muscle progenitors and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin–glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance towards the future treatment of muscular dystrophies using genetically corrected autologous induced pluripotent stem cells.

Date: 2013
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DOI: 10.1038/ncomms2550

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