Effective viral-mediated lung gene therapy: is airway surface preparation necessary?

Abstract

Gene-based therapeutics are actively being pursued for the treatment of lung diseases. While promising advances have been made over the last decades, the absence of clinically available lung-directed genetic therapies highlights the difficulties associated with this effort. Largely, progress has been hindered by the presence of inherent physical and physiological airway barriers that significantly reduce the efficacy of gene transfer. These barriers include surface mucus, mucociliary action, cell-to-cell tight junctions, and the basolateral cell membrane location of viral receptors for many commonly used gene vectors. Accordingly, airway surface preparation methods have been developed to disrupt these barriers, creating a more conducive environment for gene uptake into the target airway cells. The two major approaches have been chemical and physical methods. Both have proven effective for increasing viral-mediated gene transfer pre-clinically, although with variable effect depending on the specific strategy employed. While such methods have been explored extensively in experimental settings, they have not been used clinically. This review covers the airway surface preparation strategies reported in the literature, the advantages and disadvantages of each method, as well as a discussion about applying this concept in the clinic.

Fig. 1. Physical and physiological barriers to viral vector mediated airway gene transfer.

The airway epithelium consists of multiple barriers that limit the ability of viral vectors to deliver their transgene to the target cells. Barriers include surface mucus and the action of the mucociliary clearance (MCC); lack of relevant viral vector receptors on the apical membrane; epithelial tight junctions that prevent vector particles accessing basolateral-located receptors; and the deep-lying location of basal stem cells that are not easily accessible via the airway lumen. PCL periciliary liquid, ASL airway surface layer.

Fig. 2. Examples of physical perturbation devices.

A Blunt and fine forceps, (B) bronchial cytology brush (Cook Medical), and (C) flexible wire basket (NCircle^®, Cook Medical).