Developing an antisense oligonucleotide treatment for Spinocerebellar Ataxia Type 3

Toonen, L.J.A. (2018)

Doctoral Thesis

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 3
• Polyglutamine disorder
• Antisense oligonucleotides
• Exon skipping

• All authors: Toonen, L.J.A.
• Supervisor: Dunnen, J.T. den
• Co-supervisor: Roon-Mom, W.M.C. van
• Committee: Aartsma-Rus, A.M.; Kampinga, H.H.; Warrenburg, B. van de
• Qualification: Doctor (dr.)
• Awarding Institution: Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-05-31
• ISBN (print): 9789461828835
• Sponsorship: ADCA vereniging Nederland