Abnormally low levels of the protein alpha-1 antitrypsin caused by single-gene mutations makes individuals highly susceptible to emphysema, a progressive lung disease that causes severe shortness of breath.
Previous attempts to correct single-gene defects that cause lung disease by gene transfer have failed to achieve sustained gene expression in the mouse lung. However, a team of researchers, at Boston University School of Medicine, has now developed an approach that enabled them to attain sustained in vivo expression of normal human alpha-1 antitrypsin at levels able to improve emphysema in mice.
The team, led by Darrell Kotton, introduced gene-carrying lentiviral vectors into the windpipe of mice and found that they selectively and efficiently transferred the genes they were carrying to resident cells known as alveolar macrophages. These cells were long-lived and continued to express the transferred genes for at least two years. In a mouse model of emphysema, introduction into the windpipe of lentiviral vectors carrying the gene responsible for making normal human alpha-1 antitrypsin led to sustained alpha-1 antitrypsin expression in the lung and reduced disease. The authors therefore conclude that targeting genes to alveolar macrophages provides a way to achieve sustained gene expression in the lung and suggest that this might provide a therapeutic approach for overcoming overcome lung diseases caused by single-gene defects, for example emphysema caused by alpha-1 antitrypsin deficiency.