Barriers to Successful CF Gene Therapy

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Barriers to aerosol delivery of non-viral gene transfer agents. The surface epithelium of the large conducting airways (bronchi) is covered by a thick layer of mucus and Airway Surface Liquid (ASL). ASL comprises antimicrobial proteins, lactoferrin, lysozyme and defensins in addition to water and the epithelial glycocalyx. Neutrophils and alveolar macrophages may also be resident in this layer. The bronchi contain cartilage, smooth muscle and a large submucosal region that decreases as the airways become smaller. The epithelium of the small conducting airways (bronchioles) has a simpler, columnar/cuboidal organisation containing mainly ciliated epithelial cells and Clara cells. The gaseous exchange region is composed of the respiratory bronchioles with the epithelium interrupted by the alveolar ducts, which contain the alveolar spaces.

While the CF Cl- channel defect has been shown to be reversible in cell culture many additional extracellular barriers exist in vivo as the airway epithelia have evolved to prevent penetration by foreign materials (McCluskie & Davis 2000).

Initially the GTA carrying the transgene needs to reach the pulmonary airways where it will encounter the mucus membrane complex, which may bind the gene transfer agent (GTA) and clear it from the lung by mucociliary clearance (Boucher 1999).

If not immediately cleared from the lungs, the GTA must penetrate the mucus to gain access to the surface of the cell and then penetrate the plasma membrane (Yonemitsu et al. 2000).

In the airway, generally only the apical surface of cells is available to a GTA as tight junctions between cells restricts access to the basolateral surface.

Once the GTA has entered the cell, it must cross the cytoplasm and the DNA must enter the nucleus. Therefore a successful strategy for long term gene transfer to the apical surface of the airway epithelia must be able to overcome these barriers.

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