Dr. Dusty Miller

Our research focuses on the basic biology of retroviruses and adeno-associated viruses (AAV), with an emphasis on the application of our findings to the design and use of viral vectors in human gene therapy. Our retroviral vectors and vector packaging cell lines were used in the first human gene transfer and gene therapy trials in the U.S., and since then have been used in many gene therapy trials world-wide. Currently a major goal in the lab is treatment of lung disease associated with cystic fibrosis and alpha-1 antitrypsin deficiency, and we have found that AAV vectors promote high rates of gene transfer and expression (transduction) in lungs of animals. Prior research had focused on vectors derived from AAV2, but we have identified a new strain called AAV6 that promotes more efficient transduction of the lung and is less immunogenic than AAV2. We are currently working to obtain approval to test our AAV vectors in clinical trials.

Several years ago we became interested in jaagsiekte sheep retrovirus (JSRV) as a potential vector for lung-directed gene therapy. JSRV causes a contagious cancer in lungs of sheep, and we hypothesized that JSRV might be well-adapted to infect lung cells. Thus vectors derived from JSRV might be useful for lung gene therapy provided the oncogenic properties of the virus could be controlled. We generated several types of non-oncogenic JSRV vectors and showed that they could infect human as well as sheep cells, but in studies to date we have not seen very efficient transduction of lung cells in animals.

During our studies of JSRV we became interested in its oncogenic properties, and this area of research is now a major focus of the lab. We have shown that the envelope protein of JSRV, and that of a related sheep retrovirus called enzootic nasal tumor virus (ENTV), are the active oncogenes in these viruses. The envelope proteins mediate virus entry into cells, and we identified hyaluronidase 2 (Hyal2) is the cellular receptor that binds envelope and is required for cell entry by both viruses. We have been pursuing the hypothesis that the virus envelope interaction with this receptor contributes to oncogenesis by JSRV and ENTV. However, it appears that the cytoplasmic tails of the virus envelope proteins, and not the Hyal2-binding extracellular domains, are the key determinant of oncogenesis, and these domains activate the PI3-kinase/Akt and MAPK oncogenic pathways. We have recently shown that the JSRV or the ENTV envelope protein alone can induce lung tumors in mice. Because mouse Hyal2 does not promote entry of JSRV vectors and does not bind the envelope protein, this shows that the envelope/Hyal2 interaction is not required for oncogenesis. Future studies are aimed at detailed analysis of the oncogenic pathways induced by JSRV and ENTV in animals and the relationship of these virus-induced cancers to human lung cancer. Importantly, the type of peripheral adenocarcinoma caused by JSRV is similar in phenotype to about 25% of human lung cancers, a major cause of human cancer mortality.