Jul 1, 2022, 11:30 AM
Room: S3 A

Room: S3 A


Manzanares Sandoval, Dario (University College Dublin (UCD) )


Cystic fibrosis (CF) is a lethal autosomal recessive inherited disease caused by mutations in the CFTR gene encoding the CF transmembrane conductance regulator (CFTR) protein, and has no cure to date. CFTR gene mutations lead to abnormal chloride ion transport in epithelial tissues, which changes the hydration and pH of fluids and mucus, affecting respiratory (main cause of morbidity and mortality) and digestive systems among others [1].
Gene therapy is the most suitable approach for treating this disease. Gene replacement strategies for CF have been previously developed but failed due to low gene delivery efficiency combined with brief expression in epithelial cells. Although gene therapy based on viral vectors has been proven to be efficient, safety risks and immune response are important limitations [2]. The rise of non-viral vectors has taken place to overcome these drawbacks, however, clinical trials with liposomes have been performed and finally abandoned.
In this work, we propose a different approach that consists in the development of a non-viral gene therapy based on highly branched poly(β-amino ester)s (HPAE), which family has been previously shown to perform high transfection efficiency in other genetic conditions [2], and offers advantages compared to liposomes such as easier functionalization and higher stability and retention of the cargos [3].

A library of cationic HPAE polymers was developed, characterized, and optimized by selection of the best molecular weights, enhancement of the branched structure and the biocompatibility, and terminal group performance evaluation. Then, a screening of the candidate polymers was carried out in vitro in CF disease model cell lines in terms of cell viability and plasmid DNA transfection efficiency. Moreover, optimized CFTR gene-containing DNA plasmids were constructed to be combined with the HPAEs developed.

A family of HPAEs with different monomeric combinations and terminal groups was created and their physicochemical features were characterized. Among all these polymers developed for plasmid DNA delivery, some of them showed higher transfection efficiency than others commercially available in CF lung epithelial cell lines, with similar or higher levels of cell viability. In addition, different CFTR gene-containing DNA plasmids with different combinations of promoters and enhancers were successfully obtained as an alternative system to the gene replacement strategies currently available.

The basis for the development of a promising non-viral therapy for CF has been laid. This has been possible thanks to the synthesis of efficient gene delivery tools as are HPAE polymers combined to optimized genetic systems to restore the CFTR protein levels, regenerating thus the lung epithelial cells function. This approach offers a new perspective from the clinical trials performed to date with other non-viral vectors and is expected to be further tested in vivo as an inhalation therapy. In addition, these systems have got a high potential for future commercialization and as bench-to-bedside research.


  1. Shteinberg, M. et al.,The Lancet. 397 (10290), 2195-2211 (2021).
  2. Zeng, M. et al., Adv. Drug Deliv. Rev. 176 (1134829) (2021).
  3. Rideau, E. et al., Chem. Soc. Rev. 47 (23), 8505-8970 (2018)."


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