Gene therapy with lipid nanoparticles for Fabry disease: Leveraging E-selectin for targeted delivery to endothelial cells

Fabry disease (FD) is caused by deficiency of activity of the lysosomal enzyme α-Galactosidase A (α-Gal A) throughout the organism, and vascular dysfunction represents the main pathological event causing life-threatening complications. Therefore, endothelial cells (ECs) are currently receiving attention as potential targets for the development of innovative therapies for FD, including gene therapy. However, the difficulty of transfecting ECs poses a major challenge to the development of vascular endothelial-targeted nucleic acid delivery systems. In the present study, we have developed lipid nanoparticles (LNPs) coupled with antibodies against the E-selectin to deliver pDNA encoding α-Gal A specifically to activated ECs, which express E-selectin. Coupled LNPs showed significantly higher cell association than uncoupled LNPs in activated Human Umbilical Vein Endothelial Cells (HUVECs) and in a cellular model of FD (Immortalized Fabry Endothelial Cell Line-1 (IMFE-1)), and this was translated into a higher transfection efficacy. Additionally, in IMFE-1 cells, antibody-coupled LNPs increased α-Gal A activity to levels 6.5-fold higher than untreated cells. In conclusion, E-selectin-targeted LNPs encapsulating pDNA showed enhanced transfection efficacy in activated ECs and the ability to increase α-Gal A activity in an FD cellular model, opening the door to a new therapeutic strategy in the treatment of FD.