ASO targeting RBM3 temperature‐controlled poison exon splicing prevents neurodegeneration in vivo

Abstract 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.