Gene and cell therapy for cystic fibrosis: From bench to bedside

Abstract

Clinical trials in cystic fibrosis (CF) patients established proof-of-principle for transfer of the wild-type cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelial cells. However, the limited efficacy of gene transfer vectors as well as extra- and intracellular barriers have prevented the development of a gene therapy-based treatment for CF. Here, we review the use of new viral and nonviral gene therapy vectors, as well as human artificial chromosomes, to overcome barriers to successful CFTR expression. Pre-clinical studies will surely benefit from novel animal models, such as CF pigs and ferrets. Prenatal gene therapy is a potential alternative to gene transfer to fully developed lungs. However, unresolved issues, including the possibility of adverse effects on pre- and postnatal development, the risk of initiating oncogenic or degenerative processes and germ line transmission require further investigation. Finally, we discuss the therapeutic potential of stem cells for CF lung disease.

Chitosan as a non-viral co-transfection system in a cystic fibrosis cell line

“…Therefore, the correction of the defective CFTR gene, offers to be the most attractive solution for this disease. Gene therapy focused in the use of viral carriers has been widely studied in CF treatments due to the high transfection efficiency reported (Conese et al, 2011). However, the use of viruses as vectors raises many concerns regarding possible immune response, its biosafety and severe inflammation after long periods of administration (Griesenbach and Alton, 2012).…”

The Genetics of CFTR: Genotype - Phenotype Relationship, Diagnostic Challenge and Therapeutic Implications

“…Although, since the discovery of CFTR gene in 1989 more than 30 clinical trials of gene therapy have been undertaken, no gene therapy has been so far approved for clinical use (Conese et al, 2011;Davies & Alton, 2011;Griesenbach & Alton, 2011). The problems arose from the repeated administration of adenovirus-and adeno-associated virus-based vectors shifted the approaches to lentiviral vectors and non-viral strategies, as well as cell therapy.…”

Synthesis, characterization, and immune efficacy of layered double hydroxide@SiO2 nanoparticles with shell-core structure as a delivery carrier for Newcastle disease virus DNA vaccine

“…However, because of their high hydrophilicity and therefore a low distribution coefficient between oil and water phases, 9,10 it is difficult for DNA vaccines to transfer across cell membranes after intramuscular injection, limiting the amount of vaccine to be captured by antigen-presenting cells to induce immune responses. 11 Other factors that limit the clinical applications of these novel DNA vaccines include the difficulties associated with DNA stability and delivery, resulting in low levels of DNA vaccine expression and weak immune responses, [12][13][14] especially in large animal models. 15 Therefore, effective strategies which can improve the efficacy of DNA vaccines, such as the use of a powerful adjuvant to enhance immunogenicity, optimization of the delivery methods, and selection of suitable target for effective antigen presentation, etc, are desirable.…”