Mayo Clinic researchers working with colleagues in Germany have discovered a way to fight cancer by using parts of a virus found in tree shrews, small Southeast Asian mammals. The researchers used the virus to create a disguise for an engineered measles virus that enables it to sneak past the immune system. It kills cancer cells without harming healthy cells.
The work is still experimental. But it is a key step forward in the science of redirecting or retargeting a virus through genetic engineering. Retargeted measles virus can recognize surface molecules found only on cancerous cells, allowing selective killing. In this way, retargeted cancer-killing viruses help the body, rather than harming it as natural viruses do when they infect cells.
In the current issue of the Journal of Virology, the researchers describe how they invented a way to engineer an alternative outer covering (coat) for the virus, using pieces from an animal virus that cannot infect humans.
"Our group’s perspective is to exchange pieces on the envelope, the viral coat, with the pieces from the coat of a related virus that has no known relatives that can infect humans," says Roberto Cattaneo, Ph.D., lead researcher and an internationally recognized pioneer in viral targeting technology. "If we can modify the virus and take parts from the Tupaia paramyxovirus (the shrew virus) and put them on the measles virus, then we have a virus in stealth. It will not be recognized by the immune system because it’s disguised in another coat — and that way we can get the virus past the immune system."
Significance of the Research
A different Mayo Clinic research team was the first to engineer a measles virus retargeted at the cell entry level and reported on this earlier this year. The current investigation takes the technology a step closer to being useful to human patients by paving the way to get the retargeted measles virus past the immune system so it can actually reach the tumor and destroy it.
Background and Next Steps
Viruses are parasites. They:
- attach to, or penetrate a partner on the target cell
- fuse membranes to enter the target cell
- commandeer the cellular machinery to produce more virus
- modulate or control the host immune response
While the stealth approach works, there’s a problem — the disguise works only once because a healthy immune system is so good at its job, it makes antibodies against the modified viral coat and won’t be tricked twice. But researchers at Mayo are designing alternative disguises.
"That means we’ll have to make another coat to disguise it again, and we have already identified candidate animal viruses that can help us do that, which means we have the prospect of using the same retargeted measles virus with different coats," says Dr. Cattaneo.
Noting that safety is of utmost priority, Dr. Cattaneo stresses that multiple safeguards prevent the unintended creation of a super virus capable of causing a new human disease.
"With this paper we really make the point that there is an untapped resource in the form of animal viruses that can be used as a source of modules that can be combined with human viruses to evade the immune system," Dr. Cattaneo says. "Our lab can do this safely because we have quite an elaborate safety system — four levels of specificity — that block, interfere and provide an emergency brake to a virus’ ability to spread in normal human cells and cause illness."
Collaboration and Support
In addition to Dr. Cattaneo, the Mayo Clinic research team includes Christoph Springfeld, M.D., Dr. P.H.; and Veronika von Messling, D.V.M.; in Rochester. Collaborators in Heidelberg, Germany are Christian Tidona, Ph.D.; and Gholamreza Darai, M.D., Ph.D. The work was supported by research grants from Mayo Foundation, the Siebens Foundation and the National Institutes of Health, and a research scholarship from the German Research Foundation.
[Springfeld C. et al. Envelope targeting: hemagglutinin attachment specificity rather than fusion protein cleavage-activation restricts Tupaia paramyxovirus tropism. J. Virol.]
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