ArticleMolecular therapy. Nucleic acids2017
Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice.
Article in Molecular therapy. Nucleic acids, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.
- Assisted delivery of antisense therapeutics in animal models of heritable neurodegenerative and neuromuscular disorders: a systematic review and meta-analysis.Scientific reports · 2018Pooled it
- Optimizing twin prime editing components for scalable genome editing and therapy in spinocerebellar ataxia type 3.Molecular therapy. Nucleic acids · 2026Article
- An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.Molecular therapy. Nucleic acids · 2026Article
- Ataxin-3 Overexpression via Adeno-associated Viral Vector Injection in the Primate Cerebellum: A Novel Model of Spinocerebellar Ataxia Type 3.Experimental neurobiology · 2025Article
- Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.Human molecular genetics · 2025Article
- Genome editing in spinocerebellar ataxia type 3 cells improves Golgi apparatus structure.Scientific reports · 2025Article
- ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments.Human mutation · 2024Review
- Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3.Disease models & mechanisms · 2023Article
- Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model.bioRxiv : the preprint server for biology · 2023Article
- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- News from around the RNA world: new avenues in RNA biology, biotechnology and therapeutics from the 2022 SIBBM meeting.Biology open · 2022Article
- Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases.Pharmaceutics · 2022Review
- Lipid Dyshomeostasis and Inherited Cerebellar Ataxia.Molecular neurobiology · 2022Review
- Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives.Nucleic acid therapeutics · 2022Article
- Allele-specific targeting of mutant ataxin-3 by antisense oligonucleotides in SCA3-iPSC-derived neurons.Molecular therapy. Nucleic acids · 2022Article
- Human Induced Pluripotent Stem Cell-Based Modelling of Spinocerebellar Ataxias.Stem cell reviews and reports · 2022Review
- Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegeneration. One important function of ataxin-3 is its involvement in the proteasomal protein degradation pathway, and long-term downregulation of the protein may therefore not be desirable. In the current study, we made use of antisense oligonucleotides to mask predicted exonic splicing signals, resulting in exon 10 skipping from ATXN3 pre-mRNA. This led to formation of a truncated ataxin-3 protein lacking the toxic polyglutamine expansion, but retaining its ubiquitin binding and cleavage function. Repeated intracerebroventricular injections of the antisense oligonucleotides in a SCA3 mouse model led to exon skipping and formation of the modified ataxin-3 protein throughout the mouse brain. Exon skipping was long lasting, with the modified protein being detectable for at least 2.5 months after antisense oligonucleotide injection. A reduction in insoluble ataxin-3 and nuclear accumulation was observed following antisense oligonucleotide treatment, indicating a beneficial effect on pathogenicity. Together, these data suggest that exon 10 skipping is a promising therapeutic approach for SCA3.
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