ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo
| العنوان: | ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo |
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| المؤلفون: | Preußner, Marco, Smith, Heather L, Hughes, Daniel, Zhang, Min, Emmerichs, Ann-Kathrin, Scalzitti, Silvia, Peretti, Diego, Swinden, Dean, Neumann, Alexander, Haltenhof, Tom, Mallucci, Giovanna R, Heyd, Florian |
| المساهمون: | Preußner, Marco [0000-0001-5155-0844], Hughes, Daniel [0000-0002-9706-5163], Mallucci, Giovanna R [0000-0001-8504-1191], Heyd, Florian [0000-0001-9377-9882], Apollo - University of Cambridge Repository |
| بيانات النشر: | EMBO, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | RBM3, Temperature, RNA-Binding Proteins, Oligonucleotides, Antisense, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten, Poisons, Cold Temperature, alternative splicing coupled to nonsense-mediated decay, Mice, Humans, Animals, neurodegenerative diseases, neuroprotection, hypothermia, Aged |
| الوصف: | Funder: Freie Universität Berlin; Id: http://dx.doi.org/10.13039/501100007537Test Funder: Cambridge Centre for Parkinson's Plus Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold-induced expression. Genetic removal or antisense oligonucleotide (ASO)-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increased RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease-associated prion protein. Our promising results in mice support the possibility that RBM3-inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease. |
| وصف الملف: | text/xml; application/pdf |
| DOI: | 10.17863/cam.95240 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b39ba28f981a71d77157df7b5791b0aTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4b39ba28f981a71d77157df7b5791b0a |
| قاعدة البيانات: | OpenAIRE |
| DOI: | 10.17863/cam.95240 |
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