Abstract
Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disease for which there is currently no cure, nor effective treatment strategy. One of nine polyglutamine disorders known to date, SCA3 is clinically heterogeneous and the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected individual. SCA3 is caused by an expanded polyglutamine tract in the ataxin-3 protein, resulting in conformational changes that lead to toxic gain of function. The expanded glutamine tract is located at the 5′ end of the penultimate exon (exon 10) of ATXN3 gene transcript. Other studies reported removal of the expanded glutamine tract using splice switching antisense oligonucleotides. Here, we describe improved efficiency in the removal of the toxic polyglutamine tract of ataxin-3 in vitro using phosphorodiamidate morpholino oligomers, when compared to antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone. Significant downregulation of both the expanded and non-expanded protein was induced by the morpholino antisense oligomer, with a greater proportion of ataxin-3 protein missing the polyglutamine tract. With growing concerns over toxicity associated with long-term administration of phosphorothioate oligonucleotides, the use of a phosphorodiamidate morpholino oligomer may be preferable for clinical application. These results suggest that morpholino oligomers may provide greater therapeutic benefit for the treatment of spinocerebellar ataxia type 3, without toxic effects.
Highlights
Spinocerebellar ataxia type 3 (SCA3) is a progressive, typically late-onset autosomal dominant neurodegenerative disease [1]
We describe efficient removal of the CAG containing exon 10 to produce a truncated ataxin-3 protein, lacking the polyglutamine tract, an isoform reported by Toonen et al (2017) to be functionally active [8]
Our study shows that by using the phosphorodiamidate morpholino oligomer (PMO) chemistry, is exon 10 skipping enhanced at the RNA level, and significant downregulation of the protein with higher number of glutamine repeats and an increase in production of the truncated protein is observed, when compared to the use of the 2 -Me PS antisense oligonucleotides (AOs) chemistry
Summary
Spinocerebellar ataxia type 3 (SCA3) is a progressive, typically late-onset autosomal dominant neurodegenerative disease [1]. The expanded CAG repeat located in exon 10 of ATXN3 results in the addition of an extended glutamine tract in ataxin-3, directly leading to conformational changes that give the protein a toxic gain of function(s), as well as subjecting the protein to formation of neuronal nuclear inclusions [7]. Van Roon-Mom and colleagues have published two reports detailing the removal of the CAG containing exon in the ATXN3 transcript [8,9] These studies show removal of the CAG containing exon, and production of a functional truncated protein using a modified 2 -O-methoxy-ethyl nucleotide (2 -MOE) on a phosphorothioate (PS) backbone. With robust splice switching efficiency and an established long-term safety profile, the PMO oligomers described here are presented as lead pre-clinical candidates to treat SCA3 patients
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