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The handle http://hdl.handle.net/1887/68333 holds various files of this Leiden University

dissertation.

Author: Miniarikova, J.

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MICRORNA-BASED GENE THERAPY FOR

HUNTINGTON'S DISEASE:

SILENCING THE VILLAIN

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MicroRNA-based gene therapy for Huntington’s disease: Silencing the villain ISBN 978-94-6375-175-9

Layout: Egied Simons Cover: Seyens Printing: Ridderprint

Copyright © 2018, Jana Miniariková. All rights reserved. No parts of this thesis may be reproduced or transmitted in any form, by any means, without prior written permission of the author.

The printing of this thesis and graduation was financially supported by: uniQure

Leiden University Medical Center Baseclear

Sanbio ttopstart

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MICRORNA-BASED GENE THERAPY FOR

HUNTINGTON'S DISEASE:

SILENCING THE VILLAIN

Proefschrift

ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof.mr. C.J.J.M. Stolker,

volgens besluit van het College voor Promoties te verdedigen op donderdag 24 januari 2019

klokke 13.45 uur door

JANA MINIARIKOVÁ

geboren te Bratislava (Slowakije)

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Co-promotor: Dr. P. Konstantinova

(uniQure, Amsterdam, The Netherlands) Leden promotiecommissie: Prof. Dr. R. Hoeben

Prof. Dr. R. Roos

Prof. Dr. A. Aartsma-Rus Prof. Dr. P. H. Reitsma Prof. MVDr. J. Motlík, DrSc.

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CONTENTS

Chapter 1: General introduction - Translation of microRNA-based huntingtin 9 lowering therapies from preclinical studies to the clinic

Mol. Ther. (2018); 26: 947–962

Chapter 2: Design, characterization and lead selection of therapeutic miRNAs 37 targeting huntingtin for development of gene therapy for Huntington’s

disease

Mol. Ther. Nucleic Acids (2016); 5: e297

Chapter 3: AAV5-miHTT gene therapy demonstrates suppression of mutant 85 huntingtin aggregation and neuronal dysfunction in a rat model of

Huntington’s disease

Gene Ther. (2017); 24: 630–639

Chapter 4: Therapeutic microRNAs targeting nuclear huntingtin for a development 111 of a personalized gene therapy for Huntington’s disease

Chapter 5: Mature miHTT molecules are present in vesicles enriched for exosomes 135 and secreted from Huntington’s disease neuronal cultures treated with AAV5-miHTT gene therapy

Chapter 6: General discussion 157

Mol. Ther. (2018); 26: 947–962

Addendum: English summary 179

Dutch summary / Nederlandse samenvatting 181

Slovak summary / Zhrnutie v slovenčine 185

List of abbreviations 189

Curriculum vitae 191

Referenties

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