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

Neurodegenerative diseases become increasingly prevalent in the aging population and currently no cure is available. Increasing expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective, but hypothermia poses a health risk itself, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon that is solely responsible for temperature-controlled RBM3 expression. Genetic removal or ASO-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO, using FDA-approved chemistry, results in long-lasting increase of RBM3 expression and remarkable neuroprotection, with prevention of neuronal loss and spongiosis in prion-diseased mice. RBM3-inducing ASOs could thus broadly deliver protection in humans in conditions from acute brain injury to Alzheimer’s disease.