Refinement of antisense oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy
Heemskerk, J.A.
Citation
Heemskerk, J. A. (2011, October 26). Refinement of antisense
oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy. Retrieved from https://hdl.handle.net/1887/17986
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/17986
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Refinement of antisense oligonucleotide mediated exon skipping as therapy for
Duchenne muscular dystrophy
Hans Heemskerk
Cover: drawings by Satriyo Kurnia Printed by: Off Page
ISBN: 978-94-6182-030-3
© 2011 Hans Heemskerk. All rights reserved. Copyright of the individual chapters rests with the authors, except (parts of):
Chapter 2 and 3: John Wiley and sons Chapter 4 and 5: Nature Publishing Group Chapter 6: Humana Press
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author.
Refinement of antisense oligonucleotide mediated exon skipping as therapy for
Duchenne muscular dystrophy
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof.mr. P.F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op woensdag 26 oktober 2011 klokke 11.15 uur
door
Johannes Antonius Heemskerk
geboren te Haarlem in 1979
Promotiecommissie
Promotor: Prof. Dr. Gert-Jan B. van Ommen Co-promotor: Dr. Annemieke Aartsma-Rus Overige leden: Prof. Dr. Johan T den Dunnen
Prof. Dr. Jan Verschuuren Dr. Jennifer E Morgan
(UCL Institute of Child Health, Londen, GB)
The studies described in this thesis have been performed at the Leiden University Medical Center, department of human genetics. This work was financially supported by the Dutch Duchenne Parent Project, the Center for Biomedical Genetics, ZonMw, Senternovem, the TREAT-NMD network of excellence and Telethon Italy.
Table of contents
Chapter 1 7
General introduction
1.1 Duchenne muscular dystrophy 9
1.2 Treatment of DMD 19
1.2.1 Current treatment 19
1.2.2 Potential therapies 21
1.3 Antisense oligonucleotide mediated exon skipping 29 1.3.1Refinement of antisense oligonucleotide mediated exon skipping 32
1.4 Concluding remarks 42
1.5 References 44
Chapter 2 65
In vivo comparison of 2’-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping
Chapter 3 77
Development of antisense-mediated exon skipping as a treatment for Duchenne muscular dystrophy
Chapter 4 89
Pre-clinical PK and PD studies on 2’O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model
Chapter 5 99
Accurate quantification of dystrophin mRNA and exon skipping levels in Duchenne muscular dystrophy
Chapter 6 109
Identification of peptides for tissue specific delivery
Summary 133
Nederlandse samenvatting 136
Abbreviations 139
Curriculum vitae 140
Publication list 141
Dankwoord 142
