Trojan nanobodies to increase frataxin function

This project aims to find ways to increase frataxin by improving its stability and reducing its turnover in the cell. Iron-sulfur (Fe-S) clusters are essential cofactors present in all known forms of life and required by hundreds of proteins to perform their function. In eukaryotic cells, the biogenesis of most Fe-S clusters occurs in the mitochondria, and this process involves the interactions and activities of several proteins. One of them is frataxin, which is a key activator. In FA, frataxin expression is very low due to the presence of long GAA repeats in the gene and, in some rare cases, to the presence of small mutations that produce versions of frataxin that are destroyed very rapidly. Nanobodies (NBs) are smaller versions of antibodies produced in llamas that display high stability and can be used to target and bind proteins like frataxin. Dr. Santos and his group have selected NBs that can bind frataxin and propose that these NBs will increase the stability of unstable frataxin variants, thus increasing their level in the cell. Their hypothesis is that frataxin-specific NBs can also improve the frataxin function. They plan to create Trojan versions of NBs by fusing them with cell penetrating peptides to allow the NBs to enter cells. They will also measure the effects of these nanobodies in rescuing cellular dysfunction.