Gene therapy targeting 'cold shock protein' protects neurons from damage

A method to increase levels of a 'cold shock protein' in mice infected with prion disease has led to neuroprotective effects – without the need for cooling.

When body temperature drops significantly, like during hypothermia, there is an increase in levels of a cold shock protein, RBM3. Previously, increasing RBM3 during therapeutic hypothermia was neuroprotective in mice, but the cooling of the body limits clinical applications. However, researchers from the UK and Germany, have discovered a method to increase levels of RBM3 at normal body temperature.

'This approach offers the prospect of being able to protect against diseases such as Alzheimer's and Parkinson's disease, for which we have no reliable preventative treatments' said Professor Florian Heyd from the Institute of Chemistry and Biochemistry at Freie Universität, Berlin, Germany, who was a co-author on the study.

The study, published in EMBO Molecular Medicine, used an antisense oligonucleotide (ASO) to remove a section of the RBM3 gene that the researchers identified as preventing RBM3 protein expression in normal conditions. An ASO is a small section of DNA or RNA that binds to a gene and alters the production of target proteins. Removing the section enabled the protein to be expressed at normal body temperature.

Researchers tested their method in mice infected with prion disease. Prion disease refers to a group of rare neurodegenerative conditions caused by misfolding prion proteins that build up in the brain, infecting other brain cells and causing them to die. The diseases can progress quickly and there is no cure.

Some of the mice were injected with a single dose of the ASO three weeks after being infected with the disease, compared with others who received a control injection.

After 12 weeks, the mice treated with ASO had levels of RBM3 twofold higher than the control mice and showed neuroprotective effects despite high levels of diseased prion proteins. The mice also displayed preservation of neurons within the hippocampus, a brain region important for memory and affected in Alzheimer's disease.

Mice in the control group succumbed to their disease, showing extensive neurodegeneration throughout the brain, including neuronal loss within the hippocampus.

'Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration' said Professor Giovanna Mallucci, from the UK Dementia Research Institute and Department of Clinical Neurosciences at the University of Cambridge, who was also a co-author on the study.

'We are still a long way off this stage as our work was in mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia' added Professor Heyd. 'We are already seeing ASOs being used to successfully treat spinal muscular atrophy and they have recently been licensed to treat motor neurone disease'.