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Perverse Progress: Poliovirus as Potential Therapeutic Vehicle

Polio Eradication: Turning the Dream into Reality

Biomedical research sometimes progresses along perverse pathways. With worldwide public health experts striving to rid the world of polio and banish the poliovirus to high-containment facilities (ASM News, August 2001, p. 397), some researchers see great potential value in modified, avirulent forms of this virus, hoping to use them to address several difficult medical challenges, including spinal cord injuries and deadly brain tumors known as gliomas. Several researchers described recent progress toward those ends at the symposium "RNA Neurovirology/Gene Delivery to the CNS," held during the 101st ASM General Meeting in Orlando Fla., 20-24 May 2001, while other symposium participants described studies on similar viruses that may help to explain degenerative diseases affecting the central nervous system (CNS), particularly multiple sclerosis (see box).

Exploiting modified polioviruses is "a new strategy for treating gliomas," says Matthias Gromeier of Duke University in Durham, N.C. "We don't coerce but exploit the natural ability and unique specificity of the poliovirus."

That specificity revolves around the CD155 receptor for poliovirus that is found along surfaces of certain cells within the CNS, according to Gromeier. For the most part, poliovirus is an enteric pathogen, doing much of its replicating within the gastrointestinal tract instead of within the nervous system. However, among about 1% of those who become infected with the virus, it ranges from the gut to the CNS, where it can do devastating damage. "CD155 is responsible for that specific tropism" of this virus within the CNS, he explains. Once there, the poliovirus induces "selective damage to motor neurons in the spinal cord," causing paralysis and, sometimes, death.

Ironically, this same specificity is a "dream come true for people who work with brain tumors," Gromeier says. "CD155 is associated with every brain tumor in each of the gliomas we've analyzed"—thus making them a seemingly ready target for modified versions of the poliovirus. "Of course, we could not use wild-type virus, but we have a strategy to harness it," he says. The core of that strategy is to use a more innocuous chimeric virus, namely a replication-deficient rhinovirus that also carries the CD155-targeting capacity of poliovirus, and thus can deliver a therapeutic assault against gliomas.

"We see very efficient tumor lysis by our construct, but it can't induce polio," Gromeier continues, referring to experiments on tumors in mice that model gliomas in humans. He and his collaborators are doing a series of experiments to convince regulatory officials that the chimeric construct is unlikely to recombine or otherwise generate virulent poliovirus if administered to patients.

Meanwhile, Casey Morrow of the University of Alabama, Birmingham, also is eyeing the CD155 tropism of stripped-down versions of polioviruses as a potential means for delivering agents to repair damage to motor neurons within the CNS, such as occurs after spinal cord injuries. Much of Morrow's focus is on establishing that modified versions of poliovirus are, indeed, avirulent and how best to deliver them to critical sites within the CNS.

At first, Morrow and colleagues tested modified viruses by injecting them intracranially or into the spines of transgenic mice that carry the CD155 receptor (wild-type mice do not). Such transgenic animals are not susceptible to poliovirus by the oral route but are susceptible when the virus is injected into their spines—indeed, this test is sanctioned by World Health Organization officials as a way of certifying whether the virus used for the oral polio vaccine is suitably attenuated, according to Morrow. When more than 1 million plaque-forming units of the modified virus are injected by this route or intracranially, there is no sign of disease. However, other molecular markers indicate that the modified virus is being taken up by appropriate cells and replicating, at least transiently.

"Recently we developed a better delivery system [introducing] the virus into cerebrospinal fluid," Morrow says. Done properly, this approach avoids injuring the mice and even repeated injections in a single animal lead to "no evidence of paralysis and no behavioral or physical abnormalities," he adds. This delivery system is adaptable for expressing "foreign proteins localized within cells and, for short durations, can influence other cells in the CNS." Over the near term, a chief goal is to develop this approach as a potential means for "helping patients recover from spinal cord injuries."

Jeffrey L. Fox