Gene therapy for chronic kidney disease. Nanoparticles for antifibrotic gene delivery

Abstract

Tubulointerstitial fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD), ultimately with renal replacement therapy. So far, there is no approved antifibrotic therapy for this situation. Myofibroblasts, the effector cells of renal fibrosis, contribute to the establishment and progression of fibrogenesis. Myofibroblasts have a particularly high expression of death receptors (DR), which make them sensitive to Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) inducing cell death. TRAIL is a transmembrane protein that induces apoptosis via death receptors, playing an important role in the regulation of cell survival and inflammation. The success of TRAIL as anticancer therapy has triggered interest to investigate the role of TRAIL in other cells that undergo phenotypic and morphological differentiation, such as fibroblasts, which undergo transdifferentiation into myofibroblasts, opening up a line of investigation in fibrogenesis. In this context, strategies to block or even eradicate myofibroblasts represent an interesting alternative to prevent and/or reverse renal fibrogenesis. For this purpose, nanoparticles will be used as TRAIL gene vector to enable delivery and to allow the induction of TRAIL protein synthesis in renal tissue. This study aims to demonstrate that nanoparticle-based delivery of TRAIL therapy can be established as a new therapy for renal fibrosis through selective myofibroblast apoptosis.