Gene Therapy for Pulmonary Diseases: Research

Gene Therapy for Pulmonary Diseases: ResearchAs described for the adenovirus, some developments have involved several isoforms of the human AAV (ie, AAV2, AAV5, and AAV6), with AAV5 being more efficiently taken up by epithelial cells than AAV2. Moreover, there are other species of AAV that have recently been described such as a nonhuman primate isotype rh10, all of which allow isotype switching to avoid immune blocking and readministration to further extend the expression of genes in the lung.
Retrovirus and lentivirus vectors are able to transfect epithelial cells in culture; however, their use in vivo in the lung has been limited because of the need to deliver very high titers to effect reasonable levels of expression. In addition, retrovirus requires dividing cells for integration, while lentivirus, based on HIV and pseudotyped with the vesicular stomatitis virus (VSV) glycoprotein, can readily transfer to nondividing cells. Similar to adenovirus, the target for VSV glycoprotein interaction is at the basolateral surface of the epithelium, and transfer is mefficient. However, using the envelope glycoprotein from Ebola (Ebo) virus to pseudotype lentivirus vectors, a marked uptake of the vector through the apical surface of the epithelium is achieved in the murine lung, suggesting that this may result in a long-term expression system for the human lung (Fig 2).
Given the potential for beneficial intervention through the introduction of biologically important genes to the lung, further developments are needed in generating better and more efficient vectors and methods to circumvent the innate barriers of the lumen. New approaches may include the use of bone marrow-derived cells that have been modified to carry beneficial genes and induced to repopulate the epithelium, as was recently shown in patients who had undergone cross-gender transplantation of the lung and showed the presence of host-derived cells in the epithelium.
The lung is an attractive organ for gene transfer, because of its accessibility from both airways and vasculature. The transfer of genes via the airway results in gene expression mainly in lung epithelial cells, and the transgene is compartmentalized to the lung without much in the way of systemic distribution. In contrast, the IV application of genes transduces predominantly endothelial cells. Depending on the underlying disease, either route of administration, or even a combination of both, might be advantageous in the targeting of the lung.

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