2023 BIST Ignite Project: bRaiNA

Engineering mRNA for Specific Expression in Brain Endothelial Cells

Project overview

The multidisciplinary project bRaiNA will combine vascular biology, RNA profiling, mRNA design/synthesis, and NP-mediated mRNA delivery to achieve brain-specific mRNA expression to enhance treatment of brain disorders.

Therapeutic strategies modulating brain endothelial cells (BEC) may combat brain disorders by reversing the brain vascular dysfunction contributing to cognitive decline, or by enhancing entry of therapeutic molecules into the brain. As such, mRNA holds great potential for modulating BEC due to its efficiency of protein expression (particularly in non-proliferating cells) and lack of genomic insertion risk. However, the efficiency of mRNA strategies is limited by unspecific uptake and expression by endothelial cells of scavenging organs, particularly the liver. Therefore, achieving mRNA expression specifically in the brain vasculature will greatly enhance their clinical translation.

The expression of mRNA may be inhibited or enhanced by complimentary microRNA strands depending on whether the cell is in a proliferating or non-proliferating state, respectively. Importantly, the specialized phenotype of BEC endows them with a low rate of proliferation, while scavenging liver endothelial cells (LEC) have a high proliferation rate. The bRaiNA project aims to develop a mRNA-engineering strategy exploiting these cell-state-dependent differential effects of microRNA to suppress or enhance mRNA expression in the liver vs. brain vasculature, respectively.

The project draws on and combines different expertise. Dr. Gonzalez-Carter (IBEC) is an expert in brain vascular biology, neurodegenerative mechanisms, and nanoparticle-mediated therapeutic interventions; Dr. Gebauer is an expert in microRNA-mediated regulation of protein expression, microRNA profiling in different cellular phenotypes, single-cell analysis, and the role of RNA-binding proteins in human disease.