Abstract
The respiratory epithelium can be affected by many diseases that could be treated using aerosol gene therapy. Among these, cystic fibrosis (CF) is a lethal inherited disease characterized by airways complications, which determine the life expectancy and the effectiveness of aerosolized treatments. Beside evaluations performed under in vivo settings, cell culture models mimicking in vivo pathophysiological conditions can provide complementary insights into the potential of gene transfer strategies. Such models must consider multiple parameters, following the rationale that proper gene transfer evaluations depend on whether they are performed under experimental conditions close to pathophysiological settings. In addition, the mucus layer, which covers the epithelial cells, constitutes a physical barrier for gene delivery, especially in diseases such as CF. Artificial mucus models featuring physical and biological properties similar to CF mucus allow determining the ability of gene transfer systems to effectively reach the underlying epithelium. In this review, we describe mucus and cellular models relevant for CF aerosol gene therapy, with a particular emphasis on mucus rheology. We strongly believe that combining multiple pathophysiological features in single complex cell culture models could help bridge the gaps between in vitro and in vivo settings, as well as viral and non-viral gene delivery strategies.
Highlights
CF is induced by numerous mutations listed in a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) [2]
Gene delivery systems have to go through successive steps during their journey into the respiratory tract, which includes crossing the mucus barrier, reaching the underlying epithelium, and releasing their cargo in the cytoplasm of target cells
CF may be considered as a challenging model disease since these steps are further complicated with noticeable hurdles, including mucus dehydration and accumulation, chronic inflammation, and microbial colonization
Summary
Cystic fibrosis (CF) is one of the most common inherited genetic disorders, affecting over 70,000 people worldwide [1]. Alteration or dysfunction of the CFTR channel leads to abnormal ion transport and mucus dehydration (Figure 1A) Such dehydrated sticky mucus is responsible for the diminution of mucociliary clearance (MCC), leading to a mucosal accumulation. This mucus stagnation provides a propitious environment for bacterial colonization and infections, inducing. Pharmaceutics 2021, 13, 47 tion (Figure 1A) This mucus stagnation provides a propitious environment for bacterial colonization and infections, inducing related relatedinflammation.
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