ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo
biorxiv(2022)
摘要
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. Remarkably, 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 Alzheimers disease.
### Competing Interest Statement
A patent application has been filed in relation to this research. There are no other competing interests .
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