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Exon Skipping and Gene Transfer Restore Dystrophin Expression in Human Induced Pluripotent Stem Cells-Cardiomyocytes Harboring DMD Mutations

Lookup NU author(s): Morten Ritso, Dr Steven Laval, Dr Rita Barresi, Professor Annemieke Aartsma-Rus, Professor Hanns Lochmuller

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Abstract

With an incidence of approximate to 1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to approximate to 30% of normal levels in hiPSC-cardiomyocytes carrying exon 47-50 or 48-50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart.

Publication metadata

Author(s): Dick E, Kalra S, Anderson D, George V, Ritso M, Laval SH, Barresi R, Aartsma-Rus A, Lochmuller H, Denning C

Publication type: Article

Publication status: Published

Journal: Stem Cells and Development

Year: 2013

Volume: 22

Issue: 20

Pages: 2714-2724

Print publication date: 01/10/2013

Online publication date: 05/07/2013

Acceptance date: 29/05/2013

ISSN (print): 1547-3287

ISSN (electronic): 1557-8534

Publisher: Mary Ann Liebert, Inc. Publishers

URL: http://dx.doi.org/10.1089/scd.2013.0135

DOI: 10.1089/scd.2013.0135

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