CRG and IBEC to design new RNA therapeutics for brain disorders

Researchers at the Centre for Genomic Regulation (CRG) and the Institute for Bioengineering of Catalonia (IBEC) have received a BIST Ignite Grant to explore new ways of treating brain disorders using RNA technology. The award was announced today at the Barcelona Institute of Science and Technology (BIST) Forum, an event held at La Pedrera in Barcelona.

Brain disorders such as Alzheimer's disease often involve problems with the blood vessels in the brain. The brain vasculature is lined with specialized cells known as brain endothelial cells (BEC). These cells normally help protect the brain by shielding it from toxins and other external factors, but also represent a major obstacle for testing new drugs for brain diseases because they stop medicines from passing through.

Promising emerging therapeutics to tackle brain disorders such as Alzheimer’s disease or brain tumours involve using messenger RNA molecules, which also served as the technological basis for some of the COVID-19 vaccines. mRNA molecules work by instructing cells to make specific proteins that can help treat diseases.

However, researchers lack strategies to specifically target BEC in the brain without affecting similar cells in other organs. The mRNA molecules are prone to be ‘scavenged’ by the vasculature of organs such as the liver and spleen, reducing the efficiency of the treatment and increasing the risk of ‘off-target’ side effects.

Dr. Daniel Gonzalez-Carter (IBEC) and Dr. Fátima Gebauer (CRG) aim to overcome this challenge by using microRNAs. These are tiny RNA molecules which bind to mRNA molecules, effectively controlling how cells make proteins. Importantly, microRNAs work differently in cells that are dividing quickly (like the endothelial cells in the liver and spleen) versus cells that are not dividing (like the BEC in the brain). The project will try to exploit this difference to ensure that designer mRNA therapeutics work mainly in the brain and not in other parts of the body.

“Our goal is to understand how microRNAs work differently in brain endothelial cells compared to endothelial cells in the liver and spleen. We can use this knowledge to design mRNA molecules that interact with microRNAs increasing their expression in brain cells while decreasing it in cells of other parts of the body. This could be a significant advancement in treating brain disorders where targeted drug delivery is needed,” explains Dr. Fátima Gebauer, co-coordinator of the Genome Biology research programme at the Centre for Genomic Regulation.

The researchers will first test how microRNAs and mRNAs work together to affect protein production in brain cells versus liver/spleen cells. Next, they will analyse the microRNAs present in the endothelial cells to find the best candidates for therapeutic targeting. Finally, they will design special mRNA molecules that have binding sites for the candidate microRNAs, tuning the molecules to allow protein production as required.

“In essence, we aim to exploit the specialization of brain endothelial cells, which usually prevents efficient therapy delivery, to achieve expression of therapeutic proteins specifically in the brain. Therefore, we are turning the obstacle into an advantage. Achieving this goal will allow us to tailor an emerging therapeutic modality (i.e. mRNA therapeutics) to successfully tackle brain disorders, which are predicted to become more prevalent in the coming decades with the aging of the population,” says Dr. Daniel Gonzalez-Carter, Staff Member at the Institute for Bioengineering of Catalonia (IBEC).

The project is one of five Seed Grants awarded by BIST in this year’s Ignite Programme. The initiative, in its sixth edition this year, fosters new multidisciplinary collaborations to address important scientific and social challenges.

Image: Dr. Fatima Gebauer at the Centre for Genomic Regulation