Gene Therapy for Pulmonary Diseases: COPD and Asthma

Gene Therapy for Pulmonary Diseases: COPD and Asthmaa1-antitrypsin deficiency is a second pulmonary disease with an underlying single gene defect and a target for gene therapy. It is still unclear whether the replacement of a1-antitrypsin in patients with emphysema affects the course of the disease. Most attempts at gene replacement have been unsuccessful because of the short-term expression and the high concentrations of protein required for therapeutic efficacy.23 Recently, however, using a nonhuman primate serotype of AAV, high levels of the persistent expression of a1-antitrypsin were seen in mice, even if there was preexisting immunity to human AAV.
Although we are not aware of any directed research in gene therapy for COPD, several possibilities are imaginable. Currently, the most accepted theory for the development of COPD is protease/ antiprotease imbalance similar to emphysema due to hereditary a1-antitrypsin deficiency. Newer studies have shown that the pathogenesis of COPD involves not only elastases but also collagenases and gelati-nases. Thus, the reestablishment of the balance by overexpressing antiprotease genes is theoretically beneficial, and the levels of antiproteases required should be lower, as in patients with a1-antitrypsin deficiency. Experimental models>26 have suggested a role for a1-antitrypsin and secretory leukoprotease inhibitor in the treatment of this disorder. However, there is still need for a convincing study proving the concept of antiprotease treatment for COPD and emphysema. Neutrophils are a major source of proteases and reactive oxygen, and, because of their overabundance in COPD, gene therapy could also target adhesion molecules for neutrophils to reduce the influx of inflammatory cells into the lung parenchyma.
The benchmark for all future treatments of asthma are inhaled corticosteroids and bronchodilators, which are an established therapy for the majority of asthmatic patients.27 Gene therapy is not likely to be an alternative in the near future for these patients except for the concept of immunomodulation by gene-based vaccines. However, transient gene therapy could bring some benefit for asthmatic patients with severe disease who require high doses of systemic corticosteroids and for patients with corticosteroid-resistant asthma. T-helper (Th) type 1 cytokines are able to suppress Th2 cytokine reactions, and hence the overexpression of these mediators could be beneficial in the treatment of asthma. It has been shown28 that the gene transfer of IL-12 inhibits allergic airways disease by the suppression of the Th2 response to aerosolized ovalbumin. Interestingly, the overexpression of IL-12 also restored local antiviral immunity, which is impaired in a Th2-dominated environment. This observation has important clinical relevance when we consider that patients with obstructive airways disease often experience exacerbations during viral infections.

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