ArticleCellular and molecular life sciences : CMLS2012
Replacement of huntingtin exon 1 by trans-splicing.
Article in Cellular and molecular life sciences : CMLS, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Exploring the therapeutic potential of modulating nonsense-mediated mRNA decay.RNA (New York, N.Y.) · 2025Review
- Therapeutic targeting of RNA for neurological and neuromuscular disease.Genes & development · 2024Review
- RNA exon editing: Splicing the way to treat human diseases.Molecular therapy. Nucleic acids · 2024Review
- Programmable RNA writing with trans-splicing.bioRxiv : the preprint server for biology · 2024Article
- Alternative splicing of modulatory immune receptors in T lymphocytes: a newly identified and targetable mechanism for anticancer immunotherapy.Frontiers in immunology · 2024Review
- Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1.Biologics : targets & therapy · 2022Review
- Therapeutic applications of trans-splicing.British medical bulletin · 2020Article
- An ex vivo RNA trans-splicing strategy to correct human generalized severe epidermolysis bullosa simplex.The British journal of dermatology · 2019Article
- RNA Splicing and Disease: Animal Models to Therapies.Trends in genetics : TIG · 2019Review
- Molecular barcoding of viral vectors enables mapping and optimization of mRNARNA (New York, N.Y.) · 2018Article
- RNA Trans-Splicing Modulation via Antisense Molecule Interference.International journal of molecular sciences · 2018Article
- An RNA-targeted therapy for dystrophic epidermolysis bullosa.Nucleic acids research · 2017Article
- Optimization ofFrontiers in neuroscience · 2017Article
- Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing.Molecular therapy. Nucleic acids · 2016Article
- mRNA trans-splicing in gene therapy for genetic diseases.Wiley interdisciplinary reviews. RNA · 2016Review
- Correction of the Middle Eastern M712T mutation causing GNE myopathy by trans-splicing.Neuromolecular medicine · 2014Article
- Repair of Mybpc3 mRNA by 5'-trans-splicing in a Mouse Model of Hypertrophic Cardiomyopathy.Molecular therapy. Nucleic acids · 2013Article
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Authors and funding
6 authors.
Funding
Abstract
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a "gain-of-function" mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders.
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