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, Rita C R Perlingeiro

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1549
JournalNature communications
Volume4
DOIs
StatePublished - Apr 11 2013

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Utrophin
gene therapy
Gene therapy
Induced Pluripotent Stem Cells
Pluripotent Stem Cells
Dystrophin
Muscular Dystrophies
stem cells
Stem cells
Genetic Therapy
Muscle
muscles
mice
Glycoproteins
cells
synapses
Beauty
skeletal muscle
Muscles
Neuromuscular Diseases

Cite this

An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells. / Filareto, Antonio; Parker, Sarah; Darabi, Radbod; Borges, Luciene; Iacovino, Michelina; Schaaf, Tory; Mayerhofer, Timothy; Chamberlain, Jeffrey S.; Ervasti, James M.; McIvor, R. Scott; Kyba, Michael; Perlingeiro, Rita C R.

In: Nature communications, Vol. 4, 1549, 11.04.2013.

Research output: Contribution to journalArticle

Filareto, Antonio ; Parker, Sarah ; Darabi, Radbod ; Borges, Luciene ; Iacovino, Michelina ; Schaaf, Tory ; Mayerhofer, Timothy ; Chamberlain, Jeffrey S. ; Ervasti, James M. ; McIvor, R. Scott ; Kyba, Michael ; Perlingeiro, Rita C R. / An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells. In: Nature communications. 2013 ; Vol. 4.
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