Developing antisense oligonucleotides for Huntington disease and spinocerebellar ataxia type 3: exon skipping as a therapeutic strategy in polyglutamine diseases

Abstract

This thesis focuses on the development of therapies for Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). These hereditary neurodegenerative diseases are caused by a CAG repeat expansion in the DNA, making them eligible for treatment with antisense oligonucleotides (AONs).

By binding to pre-mRNA, AONs can interfere with splicing and induce exon skipping. Skipping an exon that encodes a toxic protein region results in the production of a modified protein lacking this harmful part. This thesis demonstrates the potential of this treatment strategy for HD and SCA3 in preclinical studies in mouse models for these diseases.

To monitor disease progression and treatment efficacy, (pre)clinical studies require measurable indicators: biomarkers. Hence, the disease processes in the blood and brain of a mouse model for HD were compared with the aim of developing blood-based biomarkers. Significant overlap was found, closely resembling the processes previously identified in the blood and brain of HD patients. Finally, unintended splicing effects of AONs for, among others, SCA3 and HD were investigated in cells using RNA sequencing. This study demonstrated that RNA sequencing can provide valuable insights into AON safety and enables the identification and prioritization of off-target effects for follow-up research.