Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons
| Autor: | Stefan Hauser, Jacob Helm, Melanie Kraft, Milena Korneck, Jeannette Hübener-Schmid, Ludger Schöls |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy / Nucleic Acids 27, 99-108 (2022). doi:10.1016/j.omtn.2021.11.015 Molecular Therapy: Nucleic Acids, Vol 27, Iss, Pp 99-108 (2022) |
| ISSN: | 2162-2531 |
| Popis: | Spinocerebellar ataxia type 3 (SCA3) is caused by an expanded polyglutamine stretch in ataxin-3. While wild-type ataxin-3 has important functions, e.g., as a deubiquitinase, downregulation of mutant ataxin-3 is likely to slow down the course of this fatal disease. We established a screening platform with human neurons of patients and controls derived from induced pluripotent stem cells to test antisense oligonucleotides (ASOs) for their effects on ataxin-3 expression. We identified an ASO that suppressed mutant and wild-type ataxin-3 levels by >90% after a singular treatment. Next, we screened pairs of ASOs designed to selectively target the mutant or the wild-type allele by taking advantage of a SNP (c.987G > C) in ATXN3 that is present in most SCA3 patients. We found ASOmut4 to reduce levels of mutant ataxin-3 by 80% after 10 days while leaving expression of wild-type ataxin-3 largely unaffected. In a long-term study we proved this effect to last for about 4 weeks after a single treatment without signs of neurotoxicity. This study provides proof of principle that allele-specific lowering of poly(Q)-expanded ataxin-3 by selective ASOs is feasible and long lasting, with sparing of wild-type ataxin-3 expression in a human cell culture model that is genetically identical to SCA3 patients. Graphical abstract Spinocerebellar ataxia type 3 (SCA3) is caused by an expanded polyglutamine stretch in ataxin-3. Our study highlights patient-derived neurons as an in vitro tool to screen and identify antisense oligonucleotides (ASOs) to selectively decrease the expression of mutant ataxin-3 as a potential treatment for SCA3. |
| Databáze: | OpenAIRE |
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