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Human Molecular Genetics, 2003, Vol. 12, No. 8 907-914
DOI: 10.1093/hmg/ddg100
© 2003 Oxford University Press

Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients

Annemieke Aartsma-Rus1, Anneke A.M. Janson1, Wendy E. Kaman1, Mattie Bremmer-Bout1, Johan T. den Dunnen1, Frank Baas2, Gert-Jan B. van Ommen1 and Judith C.T. van Deutekom1,*

1Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands and 2Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands

Received January 13, 2003; Accepted February 14, 2003

The dystrophin deficiency leading to the severely progressing muscle degeneration in Duchenne muscular dystrophy (DMD) patients is caused by frame-shifting mutations in the DMD gene. We are developing a reading frame correction therapy aimed at the antisense-induced skipping of targeted exons from the pre-mRNA. Despite introducing a (larger) deletion, an in-frame transcript is generated that allows the synthesis of a slightly shorter, but largely functional dystrophin as found in the mostly milder Becker muscular dystrophy (BMD). We have recently demonstrated both the efficacy and high efficiency of the antisense-induced skipping of numerous exons from the DMD transcript in control muscle cells. In principle, this would restore the reading frame in over 75% of the patients reported in the Leiden DMD mutation database. In this study, we in fact demonstrate the broad therapeutic applicability of this strategy in cultured muscle cells from six DMD patients carrying different deletions and a nonsense mutation. In each case, the specific skipping of the targeted exon was induced, restoring dystrophin synthesis in over 75% of cells. The protein was detectable as soon as 16 h post-transfection, then increased to significant levels at the membrane within 2 days, and was maintained for at least a week. Finally, its proper function was further suggested by the restored membranal expression of four associated proteins from the dystrophin–glycoprotein complex. These results document important progress towards a clinically applicable, small-molecule based therapy.

* To whom correspondence should be addressed. Tel: +31 715276080; Fax: +31 715276075; Email: deutekom{at}lumc.nl


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