May 302013
 
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Researchers at the Perelman School of Medicine, University of Pennsylvania have developed a new gene therapy to thwart a potential influenza pandemic.

Specifically, investigators in theGene Therapy ProgramDepartment of Pathology and Laboratory Medicine, directed by James M. Wilson, MD, PhD, demonstrated that a single dose of an adeno-associated virus (AAV) expressing a broadly neutralizing flu antibody into the nasal passages of mice and ferrets gives them complete protection and substantial reductions in flu replication when exposed to lethal strains of H5N1 and H1N1 flu virus. These strains were isolated from samples associated from historic human pandemics – one from the infamous 1918 flu pandemic and another from 2009.

Wilson, Anna Tretiakova, PhD, Senior Research Scientist, Maria P. Limberis, PhD, Research Assistant Professor, all from the Penn Gene Therapy Program, and colleagues published their findings online this week in Science Translational Medicine ahead of print. In addition to the Penn scientists, the international effort included colleagues from the Public Health Agency of Canada, Winnipeg; the University of Manitoba, Winnipeg; and the University of Pittsburgh. Tretiakova is also the director of translational research, and Limberis is the director of animal models core, both with the Gene Therapy Program.

“The experiments described in our paper provide critical proof-of-concept  in animals about a technology platform that can be deployed in the setting of virtually any pandemic or biological attack for which a neutralizing antibody exists or can be easily isolated,” says Wilson.  “Further development of this approach for pandemic flu has taken on more urgency in light of the spreading infection in China of the lethal bird strain of H7N9 virus in humans.”

At the Ready

Influenza infections are the seventh leading cause of death in the United States and result in almost 500,000 deaths worldwide per year, according to the Centers for Disease Control.  The emergence of a new influenza pandemic remains a threat that could result in a much loss of life and worldwide economic disruption.

There is also interest by the military in developing an off-the-shelf prophylactic vaccine should soldiers be exposed to weaponized strains of infectious agents in biologic warfare.

Human antibodies with broad neutralizing activity against various influenza strains exist but their direct use as a prophylactic treatment is impractical. Now, yearly flu vaccines are made by growing the flu virus in eggs. The viral envelope proteins on the exterior, namely hemagglutinin, are cleaved off and used as the vaccine, but vary from year to year, depending on what flu strains are prevalent. However, high mutation rates in the proteins result in the emergence of new viral types each year, which elude neutralization by preexisting antibodies in the body (specifically specific receptor binding sites on the virus that are the targets of neutralizing antibodies).

This approach has led to annual vaccinations against seasonal strains of flu viruses that are predicted to emerge during the upcoming season. Strains that arise outside of the human population, for example in domestic livestock, are distinct from those that normally circulate in humans, and can lead to deadly pandemics.

These strains are also not effectively controlled by vaccines developed to human strains, as with the 2009 H1N1 pandemic. The vaccine development time for that strain, and in general, was not fast enough to support vaccination in response to an emerging pandemic.

Knowing this, the Penn team proposed a novel approach that does not require the elicitation of an immune response, which does not provide sufficient breadth to be useful against any strain of flu other than the one for which it was designed, as with conventional approaches.

The Penn approach is to clone into a vector a gene that encodes an antibody that is effective against many strains of flu and to engineer cells that line the nasal passages to express this broadly neutralizing antibody, effectively establishing broad-based efficacy against a wide range of flu strains.

Read more . . .

via Perelman School of Medicine at the University of Pennsylvania
 

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