Developing an antisense oligonucleotide treatment for Spinocerebellar Ataxia Type 3

Author(s):
Toonen, L.J.A.
Published
2018
Publication type
Doctoral Thesis

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a hereditary

neurodegenerative disorder caused by a CAG triplet repeat expansion in the

ATXN3 gene. This expanded CAG repeat is translated into a toxic polyglutamine

repeat in the ataxin-3 protein. Over time, expression of the expanded ataxin-3 protein leads to neurodegeneration of particularly the cerebellum and brainstem in SCA3 patients. Currently, there is no treatment available for SCA3. In light of its monogenetic nature, SCA3 is a good candidate for genetic therapies. In the research described in this thesis, antisense oligonucleotides were tested as a potential therapy for SCA3. The antisense oligonucleotides were used to induce exon skipping at RNA level in order to remove toxic protein regions (proteolytic cleavage sites or the polyglutamine repeat) from the ataxin-3 protein. In addition to the therapeutic research, transcriptomic analysis of brain material from transgenic SCA3 mice was performed to further elucidate potential disease mechanisms underlying SCA3.

Spinocerebellar ataxia type 3Polyglutamine disorderAntisense oligonucleotidesExon skipping
Defense date
2018-05-31
Language
English
Supervisor(s)
Dunnen, J.T. den
Advisor(s)
Roon-Mom, W.M.C. van
Committee member(s)
Aartsma-Rus, A.M.; Kampinga, H.H.; Warrenburg, B. van de
Qualification
Ph.D.
Degree granting institution
Medicine, Leiden University Medical Center (LUMC), Leiden University, Leiden
hdl
1887/62616
ISBN(s)
9789461828835

Funding

Sponsorship
ADCA vereniging Nederland