biostudies-literaturePreußner MUK Dementia Research InstituteMedical Research CouncilFreie Universität Berline17157https://www.ebi.ac.uk/biostudies/studies/S-EPMC10165353biostudies-literatureUnknown15(5)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-EMBO molecular medicineASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo.PMC10165353UKDRI‐2001MRC MC_U132692719Mallucci GRScalzitti SPeretti DSwinden DNeumann APreußner MSmith HLHughes DZhang MEmmerichs AKHeyd FHaltenhof TfalseASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo.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-2023-01-01T00:00:00Z2023 May2025-04-25T22:28:05.487Z2025-04-06T09:06:17.507ZS-EPMC101653533694638510.15252/emmm.202217157