Development and characterization of non-viral vectors based on cationic niosomes to address cystic fibrosis disease by gene therapy approach
- SAINZ RAMOS, MIRIAM
- Gustavo Puras Ochoa Director
- José Luis Pedraz Muñoz Director
Universidad de defensa: Universidad del País Vasco - Euskal Herriko Unibertsitatea
Fecha de defensa: 17 de marzo de 2022
- Antonio José Leitâo das Neves Almeida Presidente/a
- Jon Zarate Sesma Secretario
- Cristina Soto-Sánchez Vocal
- Lluís Montoliu José Vocal
- Laura Saenz del Burgo Martínez Vocal
Tipo: Tesis
Resumen
Gene therapy is based on the delivery of exogenous genetic material into target cells to modulate theexpression of an altered genome in order to treat a specific disease. Lipid nanocarriers, such as niosomesbased on cationic lipids, non-ionic surfactants and ¿helper¿ components, are considered attractivecandidate for non-viral vectors due to their suitable biocompatibility and high versatility. The niosomechemical composition and their elaboration method influence the biophysical properties which have animpact on transfection efficiency and cytotoxicity. Indeed, compounds with specific properties have beenincluded to overcome some disadvantages of niosome formulations, such as chloroquine, which promotesendosomal escape. Gene therapy can be an excellent treatment for many disorders, in particular cysticfibrosis that is an autosomal monogenic recessive disease caused by different mutations in the cysticfibrosis conductance regulator (CFTR) gene. In this doctoral thesis, we focused on the development andin-depth biophysical and biological characterization of non-viral vectors based on cationic niosomes toface cystic fibrosis by gene therapy approach. The data obtained support that the inclusion of thechloroquine molecule in niosome formulations improves the biophysical properties of niosomes withenhanced transfection efficiencies and lower cytotoxicity. In addition, these niosomes are able to increasethe production of functional CFTR protein in cystic fibrosis cells. Furthermore, the development of athree-dimensional scaffold that better mimics the in vivo environment showed utility for evaluating newtreatments and different schedules of administration for cystic fibrosis.