Abstract
Cystic fibrosis (CF) is a chronic autosomic recessive syndrome, caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, a chloride channel expressed on the apical side of the airway epithelial cells. The lack of CFTR activity brings a dysregulated exchange of ions and water through the airway epithelium, one of the main aspects of CF lung disease pathophysiology. Lentiviral (LV) vectors, of the Retroviridae family, show interesting properties for CF gene therapy, since they integrate into the host genome and allow long-lasting gene expression. Proof-of-principle that LV vectors can transduce the airway epithelium and correct the basic electrophysiological defect in CF mice has been given. Initial data also demonstrate that LV vectors can be repeatedly administered to the lung and do not give rise to a gross inflammatory process, although they can elicit a T cell-mediated response to the transgene. Future studies will clarify the efficacy and safety profile of LV vectors in new complex animal models with CF, such as ferrets and pigs.
Highlights
Cystic fibrosis (CF), the most common lethal hereditary disease among Caucasians, with a prevalence of approximately one in 3500 newborns, is characterized by chronic lung infections and inflammation that results in life expectancy being reduced, treatment advances over the past several decades have raised the median predicted survival age from mid-teens in the 1970s to more than 36 years old today [1].The CF gene is located on the long arm of chromosome 7 [2] and, based on the prediction of the amino acid sequence of the encoded protein, it was termed CFTR
In vitro and in vivo studies have suggested that only 5–10% of normal CFTR function is required to reverse the chloride channel defect [13,14,15], it is not clear whether this has to be achieved in the majority of the airway epithelial cells, or whether a minority of cells expressing much higher levels would suffice
The lentivirus-based gene delivery system is constituted by four components: 1) the packaging elements like structural proteins and enzymes involved in the formation of the viral particles, derived from the gag-pol genes; 2) a posttranscriptional regulator for gag and pol expression as well as nuclear RNA export encoded by the rev gene; 3) the vector carrying the transgene to be transferred to the target cells; 4) an heterologous glycoprotein i.e., vesicular stomatitis virus glycoprotein G (VSV-G) which pseudotypes the vector in order to increase its tropism
Summary
Cystic fibrosis (CF), the most common lethal hereditary disease among Caucasians, with a prevalence of approximately one in 3500 newborns, is characterized by chronic lung infections and inflammation that results in life expectancy being reduced, treatment advances over the past several decades have raised the median predicted survival age from mid-teens in the 1970s to more than 36 years old today [1]. The CFTR amino acid sequence contained 12 domains previously recognized as membrane-spanning sequences, and in vitro gene transfer experiments demonstrated restoration of chloride channel function in cystic fibrosis pancreatic cells [4]. In vitro models of polarized human cystic fibrosis bronchial epithelial cells demonstrate an isotonic reduction in the volume of airway surface liquid, and impaired movement of the overlying mucus [10]. The importance of CFTR’s regulation of ENaC has been strengthened further by recent data demonstrating that overexpression of ENaC in a mouse model results in many of the key features of cystic fibrosis lung disease (e.g., reduction in airway surface liquid, reduced muco-ciliary clearance and increased mucus plugging of the lungs) without any direct impairment of CFTR function [12]
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