Gene Therapy for Pulmonary Diseases

Gene Therapy for Pulmonary DiseasesGene therapy, the replacement of defective or absent genes within the cell, or gene therapeutics, the use of transient administration of genes to affect function or modulate responses, are approaches to the treatment of pulmonary diseases that are gaining credibility. Cystic fibrosis (CF) and a1-antitrypsin deficiency are diseases that are associated with single gene defects and represent the obvious rationale for gene therapy of replacing the defective or absent gene. Chronic acquired respiratory disorders such as COPD, asthma, or interstitial lung diseases are considered to be the product of a variety of endogenous (polygenic) and exogenous influences, and less obviously are associated with gene replacement therapy. These chronic inflammatory conditions likely arise from an imbalance between destructive and protective mechanisms, such that transient gene therapy, or gene therapeutics, can be useful to reconstitute a homeostatic balance by the short-term overexpression of protective genes or the suppression of damaging genes. In a similar manner, recent advances in cancer biology have identified a number of tumor-associated antigens, and these can be targeted by cell-based and gene-based therapeutic vaccines for immunotherapy interventions in patients with lung cancer.
A number of different viral and nonviral vector systems are in use to transfer genes to lung tissue, most notably to the epithelial cells of the large and small airways. All show certain advantages and disadvantages (Table 1). Entry to the parenchyma is considered to be more difficult and less effective, so that most recent efforts have been directed at making the transfer to the epithelium more efficient and less inflammatory, and having extended expression. The airways contain several epithelial cell types, including ciliated cells, mucus-secreting goblet cells, Clara cells, and basal epithelial cells. An excellent series of studies by Pickles2 indicated that the mucociliary clearance system and the glycocalyx are two serious innate barriers to vector exposure to the epithelial cell surface (Fig 1). The glycocalyx is thought to hold virus at a distance to the epithelium and to make it available for uptake and destruction by alveolar macrophage. Recent studies have shown that the use of a temporary water-induced hypoosmotic shock permeabilizes the glycocalyx and epithelium sufficiently to allow access to the tight junctions of the epithelium, leading to efficient uptake. Currently, the most common vectors used for gene transfer to the lung are replication-deficient adenoviruses and synthetic liposome/DNA complexes, but advances in adeno-associated virus (AAV) and lentivirus vector technology place these vector systems in a complementary aspect for successful gene transfer.

Table 1—Advantages and Disadvantages of Currently Used Vector Systems for Lung Gene Transfer

Vector Advantage Disadvantage
Retrovirus/lentivirus Viral genes removed, no viral proteins made, integrates into host DNA (retrovirus) Possible insertional mutagenesis, cell division necessary (retrovirus), low titers
Adenovirus Efficient, transduces nondividing cells, produced in high titers Prior exposure, immune response, inefficient with repeated application
AAV Virus genes removed, no viral proteins made, safe, transduces nondividing cells Production labor-intensive, small packaging capacity for foreign DNA
Parainfluenza virus 1 Sendai virus RNA genome, targets apical surface of epithelium, replicates in cytoplasm Particles are inflammatory, induces immunity
Naked DNA Simple, nonimmunogenic, inexpensive, safe Inefficient transduction
Cationic liposomes Nonimmunogenic, repeated application possible, safe Gene expression transient and low


Figure 1. Barriers to the entry of viral and nonviral vectors for gene transfer to the lung. The glycocalyx, a dense mucus-like mixture of carbohydrate, glycoproteins, and polysaccharides that resides on the luminal surface of the epithelium of the airways, forms an innate barrier to epithelial cell penetration by both viral and nonviral vectors.

This entry was posted in Pulmonary Function and tagged a1-antitrypsin deficiency, asthma, cystic fibrosis, genetics, lung immunology.