Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease

Good news! Without cooling! Don't be shocked! 😊

"The discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent dementias, such as Alzheimer’s.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections. ...

In research ... studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.

The team examined the gene that codes for production of the cold shock protein and found that it contains a key element which under normal conditions prevents its expression.  Removing, or ‘dialling down’ this element using an ASO, results in a long-lasting boost to production of RBM3. ..."

From the 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."

Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease | University of Cambridge Scientists in Cambridge and Berlin have used a form of gene therapy to increase levels of the so-called ‘cold shock protein’ in the brains of mice, protecting them against the potentially devastating impact of prion disease.

ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo (open access)

Synopsis

Figure 1.

RBM3 intron 3 contains an evolutionary conserved heat-induced poison exon