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Translational Medicine HIV but at the encouragement of the Gates Foundation we began to consider applications of AAV vectors as countermeasures for pandemic respiratory infections such as those caused by infuenza viruses. Initially, research focused around seeking a broad neutralizing antibody, inserting it into an AAV, injecting it in the muscle, then programming the muscle to produce large quantities of the antibody, which circulates in the blood to prevent the virus from spreading upon infection. That was a nonstarter, given the substantial safety considerations. The cells would express the antibody for about a decade, based on monkey experiments, which is fne if it was effcacious and safe. However, there is no mechanism for turning off expression of the antibody gene if its expression was no longer needed, or became toxic. An insight came from an unlikely source —the ABC-TV reality series "Shark Tank," where a contestant pitched a transparent flter for preventing infections from what people inhale. The emphasis was on the importance of preventing the infection at the site where it is transmitted, i.e., the nose and proximal airway. We reviewed the literature on the pathogenesis of respiratory viral infections, which indicated that the initial site of infection is proximal (i.e., nasal, oral, or tracheal). Further progression of the disease resulted from the spread of virus into the lung through aspiration. died if they didn't. Finally, we tested the vector on ferrets with one H1N1 and one H5N1 clinical isolate and showed the same effcacy. We envision two possible applications. One approach is to test the current vector for safety and effcacy in humans, and to stockpile it for rapid deployment in the setting of a pandemic. The other is to include in the vector a second antibody effective against infuenza B, for possible development to prevent seasonal fu, at least in high risk groups such as elderly and immunecompromised patients. The vectors also present a practical, affordable platform for expressing biologics against infectious agents, and chemical and biologic weapons. We are working with the U.S. government in evaluating this approach as a ge- neric countermeasure for bio-threats. Using the same carrier and vector, you can attack several diseases by just introducing one or more antibody gene "cassettes" into the vector. Finally, this example illustrates how the tools of gene therapy which are currently being deployed in the clinic for the treatment of genetic diseases, have potential in many other settings. Pandemic Infuenza We focused on pandemic infuenza, given its acute importance. Other investigators identifed a broadly neutralizing antibody, FI6, against the virus that, if expressed at the right place and concentration, could block all forms of pandemic fu that we would envision ever emerging. The problem with seasonal infuenza vaccines is that they are only good for that season and very specifc in activity. As a result, researchers would have to guess the fora of infuenza that's going to emerge each season. The 2009 H1N1 pandemic showed that the time it takes to generate, manufacture, and distribute a traditional vaccine is too long. We cloned the FI6 gene into an AAV9 vector, which was aerosolized into mice to achieve expression in the nasal or pharyngeal area. Our initial test used a mouse-adapted strain of infuenza, aerosolized into vector-treated mice, which showed complete protection. We then tested this vector treatment in mice against a broad range of infuenza strains, focusing on those isolated from past human pandemics. Working with Gary Kobinger, Ph.D., chief, special pathogens at Public Health Agency of Canada and a former postdoctoral fellow of mine, the program obtained isolates of previous H5N1 and H1N1 infuenza, and a reconstruction of the 1918 H1N1 virus based on archived human tissue samples. The animals were administered the vector and sent to Dr. Kobinger, who brought them to his BSL-4 lab. We showed substantial effcacy against all isolates. In most cases, the animals survived if they recieved our vector, but Genetic Engineering & Biotechnology News | GENengnews.com | September 1, 2013 | 51