Advances in cell and gene-based therapies for cystic fibrosis lung disease

Abstract

Cystic fibrosis (CF) is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Direct delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. Yet, physical and host immune barriers in the lung present challenges for successful gene transfer to the respiratory tract. Advances in gene transfer approaches, tissue engineering, and novel animal models are generating excitement within the CF research field. This review discusses current challenges and advancements in viral and nonviral vectors, cell-based therapies, and CF animal models.

Figure 1

Cell types comprising the human tracheal and bronchial airway epithelium. (a) Light microscopy of hematoxylin and eosin stained bronchus airway epithelium reveals the abundance of goblet cells (G), ciliated cells (C), basal cells (B). (Bar = 50 µm). (b) Freeze fractured scanning electron microscopy separates the ciliated cell layer from basal cells and the basement membrane. The mucus or gel layer (M) overlaying the ciliated cells remains intact (Bar = 10 µm). (c) Transmission electron microscopy of human bronchial airway epithelium highlights the abundance of cilia and the morphology of goblet cells (Bar = 10 µm).

Figure 2

Schematic representation of airway epithelia and potential barriers to viral and nonviral vectors. Ciliated and nonciliated epithelia (yellow) line the conducting airway surface with their basolateral surfaces interacting with the basal lamina (green). Basal cells (orange) are an important progenitor cell type. Submucosal glands are a major source of secreted liquid, host defense factors, and mucins. The mucus (gel) layer (purple) covers the periciliary fluid (sol) layer (blue) in which cilia are submerged. Macrophages circulate in the periciliary environment and engulf inhaled particles, including vectors. Neutrophils, dendritic cells, as well as lymphocytes represent additional barriers and sentinels for the adaptive immune system in airways.