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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neurodegenerative diseases pose a growing challenge in aging populations, with limited disease-modifying treatments available.
• Therapeutic hypothermia enhances neuroprotection by increasing cold-shock protein RBM3, but systemic cooling has significant health risks.
• Targeting RBM3 upregulation at normothermia presents a promising therapeutic avenue.

Purpose of the Study:

• To identify mechanisms for increasing RBM3 expression independent of hypothermia.
• To develop a safe and effective method for sustained RBM3 upregulation in the brain.
• To evaluate the neuroprotective potential of RBM3 induction in a mouse model of prion disease.

Main Methods:

• Identification of a specific 'poison exon' in the RBM3 gene regulating cold-induced expression.
• Genetic manipulation and antisense oligonucleotide (ASO)-mediated exclusion of the poison exon.
• Assessment of RBM3 expression levels and neuroprotection in prion-diseased mice following ASO administration.

Main Results:

• Exclusion of the poison exon successfully upregulated RBM3 levels at normothermia.
• A single ASO administration led to long-lasting RBM3 expression in mouse brains.
• ASO treatment provided significant neuroprotection in prion-diseased mice, preventing neuronal loss and spongiosis.

Conclusions:

• Targeting the RBM3 poison exon offers a novel strategy for therapeutic RBM3 induction without cooling.
• RBM3-inducing ASOs demonstrate potent neuroprotective effects in a preclinical model.
• This approach holds potential for treating various neurological conditions, including acute brain injury and Alzheimer's disease.